Fab I inhibitors

ABSTRACT

Compounds are disclosed which are Fab I inhibitors and are useful in the treatment of bacterial infections.

FIELD OF THE INVENTION

[0001] This invention relates to pharmaceutically active compounds whichinhibit Fab I and are useful for the treatment of bacterial infections.

BACKGROUND OF THE INVENTION

[0002] While the overall pathway of saturated fatty acid biosynthesis issimilar in all organisms, the fatty acid synthase (FAS) systems varyconsiderably with respect to their structural organization. Vertebratesand yeast possess a FAS in which all the enzymatic activities areencoded on one or two polypeptide chains, respectively, and the acylcarrier protein (ACP) is an integral part of the complex. In contrast,in bacterial FAS, each of the reactions is catalyzed by a distinct,mono-functional enzyme and the ACP is a discrete protein. Therefore,there is considerable potential for the selective inhibition of thebacterial system by antibacterial agents.

[0003] Fab I (previously designated EnvM) functions as an enoyl-ACPreductase (Bergler, et al, (1994), J.Biol.Chem. 269, 5493-5496) in thefinal step of the four reactions involved in each cycle of bacterialfatty acid biosynthesis. In this pathway, the first step is catalyzed byβ-ketoacyl-ACP synthase, which condenses malonyl-ACP with acetyl-CoA(FabH, synthase III). In subsequent rounds, malonyl-ACP is condensedwith the growing-chain acyl-ACP (FabB and FabF, synthases I and II,respectively). The second step in the elongation cycle is ketoesterreduction by NADPH-dependent β-ketoacyl-ACP reductase (FabG). Subsequentdehydration by β-hydroxyacyl-ACP dehydrase (either FabA or FabZ) leadsto trans-2-enoyl-ACP, which in turn is converted to acyl-ACP byNADH-dependent enoyl-ACP reductase (Fab I). Further rounds of thiscycle, adding two carbon atoms per cycle, eventually lead topalmitoyl-ACP (16C), where upon the cycle is stopped largely due tofeedback inhibition of Fab I by palmitoyl-ACP (Heath, et al, (1996),J.Biol.Chem. 271, 1833-1836). Thus, Fab I is a major biosynthetic enzymeand is a key regulatory point in the overall synthetic pathway ofbacterial fatty acid biosynthesis. Therefore, Fab I is an ideal targetfor antibacterial intervention.

[0004] Studies have shown that diazaborine antibiotics inhibit fattyacid, phospholipid and lipopolysaccharide (LPS) biosynthesis and thatthe antibacterial target of these compounds is Fab I. For example,derivative 2b18 from Grassberger, et al, (1984) J. Med Chem 27, 947-953has been reported to be a non-competitive inhibitor of Fab I (Bergler,et al, (1994) J.Biol.Chem. 269, 5493-5496). Also, plasmids containingthe Fab I gene from diazaborine resistant S. typhimurium conferreddiazaborine resistance in E. coli (Turnowsky, et al, (1989)J.Bacteriol., 171, 6555-6565). Furthermore, inhibition of Fab I eitherby diazaborine or by raising the temperature in a Fab I temperaturesensitive mutant is lethal. These results demonstrate that Fab I isessential to the survival of the organism (Bergler, et al, (1994)J.Biol.Chem. 269, 5493-5496).

[0005] Recent studies have shown that Fab I is also the target for thebroad spectrum antibacterial agent triclosan (McMurry, et al, (1998)Nature 394, 531-532). A crystal structure of the E. Coli Fab I complexedwith NAD and triclosan shows that triclosan acts as a site-directed,very potent inhibitor of Fab I by mimicking its natural substrate (Levy,et al, (1999) Nature 398, 383-384). Ward, et al ((1999) Biochem. 38,12514-12525) have shown that there is no evidence for the formation of acovalent complex between Fab I and triclosan, which would be analogousto the diazaborines; triclosan differs from these compounds in that itis a reversible inhibitor of Fab I. The structural data for the complexof Fab I with NAD and triclosan provides important information about FabI as a therapeutic target.

[0006] Importantly, it has now been discovered that certain compoundsare Fab I inhibitors and have antibacterial activity, and, therefore,may be useful for the treatment of bacterial infections in mammals,particularly in man.

SUMMARY OF THE INVENTION

[0007] This invention comprises compounds, as described hereinafter,which inhibit Fab I and are useful in the treatment of bacterialinfections.

[0008] This invention is also a pharmaceutical composition comprisingcompounds of the instant invention according and a pharmaceuticallyacceptable carrier.

[0009] This invention is a method of treating bacterial infections byinhibiting Fab I. In a particular aspect, the compounds of thisinvention are useful as antibacterial agents.

DETAILED DESCRIPTION

[0010] This invention comprises compounds of the formula (I):

[0011] wherein:

[0012] R¹ is H, C₁₋₄alkyl, —C₀₋₆alkyl-Ar, —(CH₂)₁₋₃N(R′)₂, or—(CH₂)₁₋₃OR′;

[0013] R² is H, C₁₋₄alkyl or C₃₋₆cycloalkyl;

[0014] R³ is

[0015] R⁴ is H or C₁₋₄alkyl;

[0016] indicates that one of the two designated bonds is a double bondand the other is a single bond;

[0017] R⁵ is CH₂ when the bond to which it is attached is a double bond;or R⁵ is H or C₁₋₄alkyl when the bond to which it is attached is asingle bond;

[0018] R⁶ is H or C₁₋₄alkyl;

[0019] each R⁷ independently is H, C₁₋₆alkyl, —C₀₋₆alkyl-Ar,—(CH₂)₁₋₃N(R′)₂, or —(CH₂)₁₋₃OR′;

[0020] R⁸ is H or C₁₋₄alkyl;

[0021] R⁹ and R⁹′ independently are H or C₁₋₄alkyl;

[0022] R¹⁰ is C₁₋₄alkyl, N(R′)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′;

[0023] Y* is N(R′)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′;

[0024] each X independently is H, C₁₋₄alkyl, CH₂OH, OR′, SR′, CN,N(R′)₂, CH₂N(R′)₂, NO₂, CF₃, CO₂R′, CON(R′)₂, COR′, NR′C(O)R′, F, Cl,Br, I or —S(O)_(r)CF₃;

[0025] X* is —CH₂)₁₋₃C(O)N(R′)′(CH₂)₁₋₃-Ar or—(CH₂)₁₋₃C(O)N(R′)′(CH₂)₁₋₃-Het;

[0026] W is S or O;

[0027] Q is H or C₁₋₄alkyl;

[0028] each R′ independently is H, C₁₋₆alkyl, —C₀₋₆alkyl-Ar or—C₀₋₆alkyl-Het; and

[0029] r is 0, 1 or 2;

[0030] or a pharmaceutically acceptable salt thereof.

[0031] Additionally, this invention comprises compounds of formula (II):

[0032] wherein:

[0033] R¹ is H or C₁₋₄alkyl;

[0034] R² is H, C₁₋₄alkyl or C₃₋₆cycloalkyl;

[0035] R³ is

[0036] R⁴ is H or C₁₋₄alkyl;

[0037] indicates that one of the two designated bonds is a double bondand the other is a single bond;

[0038] R⁵ is CH₂ when the bond to which it is attached is a double bond;or R⁵ is H or C₁₋₄alkyl when the bond to which it is attached is asingle bond;

[0039] R⁶ is H or C₁₋₄alkyl;

[0040] R⁷ is H, C₁₋₆alkyl or —C₀₋₆alkyl-Ar;

[0041] Y is H, C₁₋₄alkyl, N(R)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′;

[0042] each X independently is H, C₁₋₄alkyl, CH₂OH, OR′, SR′, CN,N(R′)₂, CH₂N(R)₂, NO₂, CF₃, CO₂R′, CON(R′)₂, COR′, NR′C(O)R′, F, Cl, Br,I or -S(O)_(r)CF₃;

[0043] W is S or O;

[0044] Q is H or C₁₋₄alkyl;

[0045] M is CH₂ or O;

[0046] L is CH₂ or C(O);

[0047] E is O or NR′;

[0048] each R′ independently is H, C₁₋₆alkyl or —C₀₋₆alkyl-Ar; and

[0049] r is 0, 1 or 2;

[0050] or a pharmaceutically acceptable salt thereof.

[0051] Also, this invention comprises compounds of formula (III):

[0052] wherein:

[0053] D¹ to D⁵ form an accessible substituted seven-membered ring,which may be saturated or unsaturated, optionally containing up to twoheteroatoms chosen from the group of O, S and N wherein S and N may beoptionally oxidized;

[0054] R¹¹ is C₁₋₆alkyl; and

[0055] R″ is H or C₁₋₆alkyl;

[0056] or a pharmaceutically acceptable salt thereof.

[0057] This invention includes, but is not limited to, the followingcompounds:

[0058](E)-3-(6-aminopyridin-3-yl)-N-(4,6-dichloro-1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide;

[0059](E)-3-(2-aminopyrimidin-5-yl)-N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0060](E)-3-(6-aminopyridin-3-yl)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0061](E)-3-(6-aminopyridin-3-yl)-N-(1-isopropyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0062](E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-[6-(pyridin-2-ylamino)pyridin-3-yl]acrylamide;

[0063](E)-3-(6-aminopyridin-3-yl)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0064](E)-3-(6-aminopyridin-3-yl)-N-(3,3-dimethyl-3H-indene-1-ylmethyl)-N-methylacrylamide;

[0065](E)-3-(2-aminopyrimidin-5-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide;

[0066](E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0067](E)-N-methyl-N-(2-methylbenzo[b]thiophen-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0068] (E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide;

[0069](E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide;

[0070](E)-3-(3,4-dihydro-2H-pyrido[3,2-b)-1,4-oxazin-7-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide;

[0071] (E)-N-(1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0072](E)-3-(6-aminopyridin-3-yl)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0073](E)-3-(6-aminopyridin-3-yl)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0074](E)-3-(6-aminopyridin-3-yl)-N-(1H-indol-3-ylmethyl)-N-methylacrylamide

[0075](E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0076](E)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;

[0077](E)-3-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0078](E)-N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0079](E)-3-(6-aminopyridin-3-yl)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0080](E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide;

[0081](E)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide;

[0082](E)-N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0083](E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0084](E)-3-[6-amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;

[0085](E)-N-(2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0086](E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b)pyridin-5-yl)acrylamide;

[0087](E)-N-(1-ethyl-5-fluoro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0088](E)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0089](E)-3-(6-aminopyridin-3-yl)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0090](E)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0091](E)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0092](E)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0093](E)-3-(6-aminopyridin-3-yl)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0094](E)-3-(6-aminopyridin-3-yl)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0095](E)-3-(6-aminopyridin-3-yl)-N-(5-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0096](E)-3-(6-aminopyridin-3-yl)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0097](E)-N-methyl-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;

[0098](E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;

[0099](E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;

[0100](E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;

[0101](E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide;

[0102](E)-2,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0103](E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0104](E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;

[0105](E)-3,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0106](E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0107](E)-3-(6-aminopyridin-3-yl)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0108](E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0109](E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0110](E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0111](E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide;

[0112](E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;

[0113](E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0114](E)-3-(6-aminopyridin-3-yl)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0115](E)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0116](E)-N-(5-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0117](E)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0118](E)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0119](E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0120](E)-3-(6-aminopyridin-3-yl)-N-(7-carboxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0121](E)-N-(1,7-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0122](E)-N-(1,6-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0123](E)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0124](E)-N-(3,3-dimethyl-3H-indene-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0125](E)-N-(1,5-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0126](E)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0127](E)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0128]N-Methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e]-1,4-diazepin-7-yl)acrylamide;

[0129](E)-N-[1-(2-hydroxyethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0130](E)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0131](E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;

[0132](E)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0133](E)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0134](E)-N-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0135](E)-N-(naphthalen-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0136](E)-N-(quinolin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0137](E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-amino-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0138](E)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0139](E)-N-(naphthalen-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0140](E)-N-(benzofuran-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0141](E)-3-(6-aminopyridin-3-yl)-N-(6-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;

[0142](E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl]acrylamide;

[0143](E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide;

[0144](E)-3-(6-aminopyridin-3-yl)-N-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methylacrylamide;

[0145] (E)-N-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0146](E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)acrylamide;

[0147](E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)acrylamide;

[0148](E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)acrylamide;

[0149](E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0150](E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0151](E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0152](E)-3-(6-aminopyridin-3-yl)-N-(benzofuran-3-ylmethyl)-N-methylacrylamide;

[0153](E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide;

[0154](E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)acrylamide;

[0155](E)-N-(benzofuran-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0156](E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0157](E)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0158](E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]acrylamide;

[0159](E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]acrylamide;

[0160](E)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;and

[0161](E)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;

[0162] or a pharmaceutically acceptable salt thereof.

[0163] Also included in this invention are pharmaceutically acceptableaddition salts and complexes of the compounds of this invention. Incases wherein the compounds of this invention may have one or morechiral centers, unless specified, this invention includes each uniqueracemic compound, as well as each unique nonracemic compound.

[0164] In cases in which compounds have unsaturated carbon-carbon doublebonds, both the cis (Z) and trans (E) isomers are within the scope ofthis invention. In cases wherein compounds may exist in tautomericforms, such as keto-enol tautomers, such as

[0165] and

[0166] each tautomeric form is contemplated as being included withinthis invention, whether existing in equilibrium or locked in one form byappropriate substitution with R′. The meaning of any substituent at anyone occurrence is independent of its meaning, or any other substituent'smeaning, at any other occurrence.

[0167] Also included in this invention are prodrugs of the compounds ofthis invention. Prodrugs are considered to be any covalently bondedcarriers which release the active parent drug in vivo.

[0168] The compounds of this invention inhibit Fab I. Inhibition of thisenzyme is useful in the treatment of bacterial infections. Also, thecompounds of this invention may be useful as antifungal agents.Additionally, the compounds may be useful in combination with knownantibiotics.

[0169] Abbreviations and symbols commonly used in the peptide andchemical arts are used herein to describe the compounds of thisinvention.

[0170] C₁₋₄alkyl as applied herein means an optionally substituted alkylgroup of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl and t-butyl. C₁₋₆alkyl additionallyincludes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simplealiphatic isomers thereof. C₀₋₄alkyl and C₀₋₆alkyl additionallyindicates that no alkyl group need be present (e.g., that a covalentbond is present).

[0171] Any C₁₋₄alkyl or C₁₋₆ alkyl may be optionally substituted withthe group Rx, which may be on any carbon atom that results in a stablestructure and is available by conventional synthetic techniques.Suitable groups for Rx are C₁₋₄alkyl, OR′, SR, CN, N(R′)₂, CH₂N(R′)₂,—NO₂, —CF₃, —CO₂R′—CON(R′)₂, —COR′, —NR′C(O)R′, F, Cl, Br, I, or—S(O)_(r)CF₃, wherein R′ and r are as defined for formula (I) compounds.

[0172] Halogen or halo means F, Cl, Br, and I.

[0173] Ar, or aryl, as applied herein, means phenyl or naphthyl, orphenyl or naphthyl substituted by one to three substituents, such asthose defined above for alkyl, or substituted by methylenedioxy.

[0174] Het, or heterocycle, indicates an optionally substituted five orsix membered monocyclic ring, or a nine or ten-membered bicyclic ringcontaining one to three heteroatoms chosen from the group of nitrogen,oxygen and sulfur, which are stable and available by conventionalchemical synthesis. Illustrative heterocycles are benzofuryl,benzimidazolyl, benzopyranyl, benzothienyl, furyl, imidazolyl,indolinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl,pyrrolidinyl, tetrahydropyridinyl, pyridinyl, thiazolyl, thienyl,quinolinyl, isoquinolinyl, and tetra- and perhydro- quinolinyl andisoquinolinyl. Any accessible combination of up to three substituents onthe Het ring, such as those defined above for alkyl, that are availableby chemical synthesis and are stable are within the scope of thisinvention.

[0175] Certain radical groups are abbreviated herein. t-Bu refers to thetertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical,Fmoc refers to the fluorcnylmethoxycarbonyl radical, Ph refers to thephenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn refersto the benzyl radical, Me refers to methyl, Et refers to ethyl, Acrefers to acetyl, Alk refers to C₁₋₄alkyl, Nph refers to 1- or2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.

[0176] Certain reagents are abbreviated herein. DCC refers todicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, EDCrefers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride,HOBt refers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran,DIEA refers to diisopropylethylamine, DEAD refers to diethylazodicarboxylate, PPh₃ refers to triphenylphosphine, DIAD refers todiisopropyl azodicarboxylate, DME refers to dimethoxyethane, DMF refersto dimethylformamide, NBS refers to N-bromosuccinimide, Pd/C refers to apalladium on carbon catalyst, PPA refers to polyphosphoric acid, DPPArefers to diphenylphosphoryl azide, BOP refers tobenzotriazol-1-yloxy-tris(dimethyl-amino)phosphoniumhexafluorophosphate, HF refers to hydrofluoric acid, TEA refers totriethylamine, TFA refers to trifluoroacetic acid, PCC refers topyridinium chlorochromate.

[0177] In particular, compounds of this invention are prepared by thegeneral methods described in the Schemes hereinafter:

[0178] A suitable haloaromatic derivative, for instance2-amino-5-bromopyridine (I-1), reacts with an appropriateα,β-unsaturated ester, for example benzyl acrylate, in a Heck-typereaction (see Heck, Org. Reactions 1982, 27, 345) to afford I-2. Thereaction is mediated by a palladium(0) species, and generally isconducted in an inert solvent, such as CH₃CN, propionitrile, or toluene,in the presence of an appropriate acid scavenger, such as triethylamine(Et₃N) or diisopropylethylamine ((i-Pr)₂NEt). Typical sources of thepalladium(0) species include palladium (II) acetate (Pd(OAc)₂) andpalladium(II) chloride (PdCl₂), and oftentimes phosphine ligands, forinstance triphenylphosphine (PPh₃) or tri-ortho-tolylphosphine(P(tol)3), are included. The ethyl ester of I-2 is hydrolyzed usingaqueous base, for example, LiOH in aqueous THF or NaOH in aqueousmethanol or ethanol, and the intermediate carboxylate salt is acidifiedwith a suitable acid, for instance TFA or HCl, to afford the carboxylicacid I-3. The carboxylic acid of I-3 is converted to an activated formusing, for example, EDC and HOBt, or SOCl₂, and the activated form issubsequently reacted with an appropriate amine, for instance1-methyl-2-(methylaminomethyl)indole, in a suitable solvent such as DMF,CH₂Cl₂, or CH₃CN, to afford I-4. Depending on whether acidneutralization is required, an added base, such as triethylamine (Et₃N),diisopropylethylamine ((i-Pr)₂NEt), or pyridine, may be used. Manyadditional methods for converting a carboxylic acid to an amide areknown, and can be found in standard reference books, such as “Compendiumof Organic Synthetic Methods”, Vol. I-VI (published byWiley-Interscience), or Bodansky, “The Practice of Peptide Synthesis”(published by Springer-Verlag).

[0179] The amine coupling partners used in the present invention wereprepared by established methods well-known to those of skill in the art.For example, amine II-4 is prepared by the straightforward procedureoutlined in Scheme II. Commercially available ethyl indole-2-carboxylate(II-1) is deprotonated with a suitable base, generally sodium hydride(NaH), and the intermediate sodium salt is reacted with an appropriatealkylating agent, for instance methyl iodide, to afford II-2. Polarsolvents such as DMF, THF, or mixtures thereof are generally preferredfor this reaction. Compound II-2 can be conveniently converted to II-3by reaction with an excess of an amine, such as methylamine, in a polarsolvent, generally H₂O or a mixture of H₂O and methanol. Alternatively,the ester of II-2 can be saponified under standard conditions, typicallywith an alkali metal hydroxide such as LiOH, NaOH, or KOH, in an aqueoussolvent, such as THF, ethanol, or methanol, and the resulting carboxylicacid can be converted to the desired amide. Typical methods for formingamides are described in Scheme I. Reduction of the amide II-3 to theamine II-4 is typically accomplished with lithium aluminum hydride(LiAlH₄) in refluxing THF, although many other methods can be used toreduce amides to amines. Such methods are well-known to those of skillin the art, and can be found in standard reference volumes, such as“Compendium of Organic Synthetic Methods” (published byWiley-Interscience).

[0180] The amine coupling partners used in the present invention canalso be prepared by the reductive amination of an appropriate aldehyde(Scheme III). This method, which is well-known to those of skill in theart, involves the initial conversion of an aldehyde to an intermediateimine, which is subsequently reduced, oftentimes in situ, to afford theamine. For example, the commercially-available aldehyde III-1 reactswith an appropriate amine, for instance methylamine, in a suitablesolvent, typically methanol, to afford the imine III-2. Reaction ofIII-2 with a suitable reducing agent, for example sodium borohydride,sodium cyanoborohydride or sodium (triacetoxy)borohydride, gives theamine III-3.

[0181] Commercially available 2-aminonicotinic acid (IV-1) is reduced toalcohol IV-2 under standard conditions (LiAlH₄, THF), and the aromaticring of IV-2 is brominated using, for example, bromine orN-bromosuccinimide (NBS), in a suitable solvent such as CH₂Cl₂, aceticacid (AcOH), or mixtures thereof, to afford IV-3. On reaction with 48%aqueous HBr, IV-3 is converted to bromide IV-4, which reacts with adiester of malonic acid, for instance dimethyl malonate, under basicconditions, to afford the naphthyridone derivative IV-5. Typical basicconditions include an alkali metal hydride, for instance sodium hydride,in a neutral solvent such as DMF, THF, or mixtures thereof, or an alkalimetal alkoxide, such as sodium methoxide or sodium ethoxide, in analcoholic solvent such as with methanol or ethanol. Saponification andneutralization under standard conditions affords an intermediatecarboxylic acid (not shown), which is typically not isolated, but issubject to decarboxylation on gentle warming to afford the naphthyridoneIV-6. This compound reacts with acrylamide IV-8 in a Heck-type reactionas described in Scheme I to afford IV-9. Alternatively, IV-6 might beconverted to IV-9 according to the general procedure described in SchemeI for the conversion of 1-1 to 1-4. The acrylamide IV-8 is convenientlyprepared by reaction of amine IV-7 (see Scheme I) with an activated formof acrylic acid in an amide bond-forming reaction. Typical conditionsfor the formation of amides are described in Scheme I, and arewell-known to those of skill in the art.

[0182] Benzylic bromide V-1, prepared as described in Scheme IV, reactswith an amine, for example aqueous methylamine, to afford benzylic amineV-2. Polar solvents such as THF, DMF, DMSO, or mixture thereof, aregenerally preferred for this reaction. V-2 reacts with a dialkylcarbonate, preferably dimethyl carbonate, in the presence of a suitablebase, typically sodium methoxide, in an alcoholic solvent, generallymethanol, to afford the cyclic urea derivative V-3. This compound isconverted to V-4 by reaction with compound IV-8 as described in SchemeIV.

[0183] The nitro group of commercially available2-amino-5-bromo-3-nitropyridine (VI-1) is reduced under standardconditions using, for example, tin (II) chloride in EtOH. The resultingdiamine, VI-2, reacts with formic acid, or an appropriate equivalent, toafford the imidazopyridine derivative VI-3. This compound is convertedto a suitably protected derivative, for instance the N-trityl protectedderivative VI-4, by reaction with trityl chloride in the presence of anappropriate base, typically triethylamine or diisopropylethylamine.Typical solvents for this reaction include CH₂Cl₂, DMF, or mixturesthereof. The protecting group for the amine must be compatible withsubsequent chemistry, and must be readily removable when desired.Methods for the protection of amines are well-known to those of skill inthe art, and are described in standard reference volumes, such as Greene“Protective Groups in Organic Synthesis” (published byWiley-Interscience). VI-4 is converted to VI-5 according to the generalprocedure described in Scheme I. The trityl protecting group is removedunder standard acidic conditions (see Greene above), and the ester issaponified as in Scheme I to afford VI-6.

[0184] Commercially-available tetrahydroquinoline (VII-1) is condensedwith an appropriate aldehyde, typically benzaldehyde (PhCHO), understandard conditions to afford the olefinic derivative VII-2. Oxidativecleavage of the exocyclic olefin affords ketone VII-3. Generally,ozonolysis in a neutral solvent, such as methylene chloride (CH₂Cl₂),methanol (MeOH), or mixtures thereof, followed by in situ reduction ofthe intermediate ozonide with an appropriate reducing agent, usuallydimethylsulfide, is the method of choice for this transformation.Compound VII-3 is converted to the 7-membered lactam derivative VII-6 asdescribed by Jossang-Yanagida and Gansser (J. Het. Chem. 1978, 15,249-251). This procedure involves conversion of the ketone of VII-3 tothe corresponding oxime VII-4, which is subsequently converted to theO-tosyl derivative VII-5. A Beckmann-type rearrangement of VII-5 affordsthe lactam VII-6. Bromination of VII-6 with a suitable brominatingagent, such as bromine (Br₂) or N-bromosuccinimide (NBS), affords thebromo derivative VII-7. Typical solvents for a bromination reactioninclude CH₂Cl₂, CCl₄, MeOH, AcOH, or mixtures thereof. Bromide VII-7reacts with an appropriate α,β-unsaturated ester, for example tert-butylacrylate, in a Heck-type reaction as described in Scheme I to affordVII-8. The tert-butyl ester of VII-8 is cleaved to the correspondingcarboxylic acid VII-9 under standard acidic conditions. Typicalconditions for this transformation are described in standard referencevolumes, such as Greene “Protective Groups in Organic Synthesis”(published by Wiley-Interscience). VII-9 is converted to VII-10 by thegeneral method described in Scheme I.

[0185] Compound VIII-1, prepared as described in Scheme V, reacts withtwo equivalents of an appropriate acylating agent, preferablydi-tert-butyl dicarbonate, to afford VIII-2. As discussed in Scheme VI,the protecting group for the amines must be compatible with subsequentchemistry, and must be readily removable when desired. VIII-2 isdeprotonated with a suitable base, generally sodium hydride (NaH), andthe intermediate sodium salt is reacted with an appropriate alkylatingagent, for instance ethyl bromoacetate, to afford VIII-3. Polar solventssuch as DMF, THF, or mixtures thereof are generally preferred for thisreaction. The Boc protecting groups are removed under standard acidicconditions (see Greene above) to afford VIII-4, which undergoescyclization to compound VIII-5 on exposure to a suitable base, typicallytriethylamine (Et₃N) or diisopropylethylamine ((i-Pr)₂NEt). An inertsolvent, such as toluene, is preferred. VIII-5 is converted to VIII-6 bythe general method described in Scheme IV.

[0186] Commercially available 2,5-dibromopyridine (IX-1) reacts with2-aminopyridine in the presence of a suitable base, typically sodiumtert-butoxide, to afford the dipyridylamine derivative IX-2. Thereaction is mediated by a suitable palladium (0) catalyst, such astris(dibenzylideneacetone)dipalladium(0), in the presence of anappropriate ligand, for example 1,3-bis(diphenylphosphino)propane. Aneutral solvent such as toluene is preferred.

[0187] Benzylic bromide V-1, prepared as described in Scheme IV, reactswith an appropriate a-aminoester equivalent, for exampleN-(diphenylmethylene)glycine ethyl ester, under basic conditions, toprovide X-2. A polar, aprotic solvent, such as DMF, THF, DME, ormixtures thereof, is generally preferred, and sodium hydride istypically the base of choice, although LDA or LiN(TMS)₂ might also beused. Alternatively, the reaction might be conducted in an alcoholicsolvent, such as methanol or ethanol, with an alkali metal alkoxide, forexample sodium methoxide or sodium ethoxide, as the base. Thediphenylmethylene group is conveniently removed under acidic conditions,such as HCl in aqueous dioxane. Other conditions for the removal of adiphenylmethylene group are known to those of skill in the art, and canbe found in the chemical literature or in standard reference volumes,such as Greene (see above).

[0188] Acid addition salts of the compounds are prepared in a standardmanner in a suitable solvent from the parent compound and an excess ofan acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric,phosphoric, acetic, trifluoroacetic, maleic, succinic ormethanesulfonic. Certain of the compounds form inner salts orzwitterions which may be acceptable. Cationic salts are prepared bytreating the parent compound with an excess of an alkaline reagent, suchas a hydroxide, carbonate or alkoxide, containing the appropriatecation; or with an appropriate organic amine. Cations such as Li⁺, Na⁺,K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄ ⁺ are specific examples of cations present inpharmaceutically acceptable salts.

[0189] This invention also provides a pharmaceutical composition whichcomprises a compound according to the instant invention and apharmaceutically acceptable carrier. Accordingly, the compounds of thepresent invention may be used in the manufacture of a medicament.Pharmaceutical compositions of the compounds of this invention preparedas hereinbefore described may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation may be a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, standard 5% dextrose in water or bufferedsodium or ammonium acetate solution. Such formulation is especiallysuitable for parenteral administration, but may also be used for oraladministration or contained in a metered dose inhaler or nebulizer forinsufflation. It may be desirable to add excipients such aspolyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethyleneglycol, mannitol, sodium chloride or sodium citrate.

[0190] Alternately, these compounds may be encapsulated, tableted orprepared in a emulsion or syrup for oral administration.Pharmaceutically acceptable solid or liquid carriers may be added toenhance or stabilize the composition, or to facilitate preparation ofthe composition. Solid carriers include starch, lactose, calcium sulfatedihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin,acacia, agar or gelatin. Liquid carriers include syrup, peanut oil,olive oil, saline and water. The carrier may also include a sustainedrelease material such as glyceryl monostearate or glyceryl distearate,alone or with a wax. The amount of solid carrier varies but, preferably,will be between about 20 mg to about 1 g per dosage unit. Thepharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulating, andcompressing, when necessary, for tablet forms; or milling, mixing andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of a syrup, elixir, emulsion or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly p.o. or filled into a soft gelatin capsule.

[0191] For rectal administration, the compounds of this invention mayalso be combined with excipients, such as cocoa butter, glycerin,gelatin or polyethylene glycols, and molded into a suppository.

[0192] For topical administration, the compounds of this invention maybe combined with diluents to take the form of ointments, gels, pastes,creams, powders or sprays. The compositions which are ointments, gels,pastes or creams contain diluents, for example, animal and vegetablefats, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures of these substances. The compositions which arepowders or sprays contain diluents, for example, lactose, talc, silicicacid, aluminum hydroxide, calcium silicate and polyamide powder, ormixtures of these substances. Additionally, for topical ophthalmologicadministration, the typical carriers are water, mixtures of water andwater miscible solvents, such as lower alkanols or vegetable oils, andwater-soluble non-toxic polymers, for example cellulose derivatives,such as methyl cellulose.

[0193] The compounds described herein are inhibitors of Fab I, and areuseful for treating bacterial infections. For instance, these compoundsare useful for the treatment of bacterial infections, such as, forexample, infections of upper respiratory tract (e.g. otitis media,bacterial tracheitis, acute epiglottitis, thyroiditis), lowerrespiratory (e.g. empyema, lung abscess), cardiac (e.g. infectiveendocarditis), gastrointestinal (e.g. secretory diarrhoea, splenicabscess, retroperitoneal abscess), CNS (e.g. cerebral abscess), eye(e.g. blepharitis, conjunctivitis, keratitis, endophthalmitis, preseptaland orbital cellulitis, darcryocystitis), kidney and urinary tract (e.g.epididymitis, intrarenal and perinephric abscess, toxic shock syndrome),skin (e.g. impetigo, folliculitis, cutaneous abscesses, cellulitis,wound infection, bacterial myositis), and bone and joint (e.g. septicarthritis, osteomyelitis). Also, the compounds of this invention may beuseful as antifungal agents. Additionally, the compounds may be usefulin combination with known antibiotics.

[0194] The compounds of this invention are administered to the patient,in a manner such that the concentration of drug is sufficient to treatbacterial infections. The pharmaceutical composition containing thecompound is administered at an oral dose of between about 10 mg to about1000 mg, taken once or several times daily, in a manner consistent withthe condition of the patient. Preferably, the oral dose would be about50 mg to about 500 mg, although the dose may be varied depending uponthe age, body weight and symptoms of the patient. For acute therapy,parenteral administration is preferred. An intravenous infusion of thecompound of formula (I) in 5% dextrose in water or normal saline, or asimilar formulation with suitable excipients, is most effective,although an intramuscular bolus injection is also useful. The preciselevel and method by which the compounds are administered is readilydetermined by one skilled in the art.

[0195] The compounds may be tested in one of several biological assaysto determine the concentration of compound which is required to have agiven pharmacological effect.

[0196] Cloning of S. aureus FabI:

[0197] The fabI gene was cloned from the chromosomal DNA of S. aureusstrain WCUH29 using the polymerase chain reaction. Amplification wasperformed using Taq DNA polymerase (BRL) and the following primers:5′-CGCCTCGAGATGTTAAATCTTGAAAACAAAACATATGTC-3′ and5′-CGCGGATCCAATCAAGTCAGGTTGAAATATCCA-3′ (XhoI and BamHI sitesunderlined). The resulting fragment was then digested with XhoI andBamHI and ligated into XhoI- and BamHI-digested expression vectorpET-16b (Novagen), producing pET-His₁₀h-fabI. The gene sequence of fabIwas confirmed by automated cycle sequencing using an Applied Biosystemsmodel 377 machine. The untagged version of pET-fabI was constructed bydigesting pET-His₁₀-fabI with NcoI and NdeI to remove a 97 bp fragmentencoding the His 10 tag, the factor Xa cleavage site and the first 8amino acids of FabI, and replacing it with a linker encoding the first 8amino acids of FabI plus a glycine residue between the initiatormethionine and the lysine at position 2. This plasmid was calledpET-fabI. The linker was made by annealing the following twooligonucleotides: 5′-CATGGGCTTAAATCTTGAAAACAAAACA-3′ and5′-TATGTTTTGTTTTCAAGATTTAAGCC-3′. The linker sequence in pET-fabI wasconfirmed by dideoxy sequencing. Only native FabI was used for compoundevaluation. For overproduction of native FabI, plasmid pET-fabI wastransformed into BL21(DE3) (Novagen) cells, to form strainBL21(DE3):pET-fabI.

[0198] Purification of S. aureus FabI

[0199]S. aureus FabI was expressed as soluble protein to 10% of totalcell protein, 400 g cells being recovered from 15L fermentation intryptone phosphate medium. The cells were lysed and the samplecentrifuged. The resulting supernatant was filtered and purified usingthree consecutive chromatography columns: ion-exchange (Sourse 15Q),dye-affinity (Blue sepharose), and size exclusion chromatography columns(Superose 12). After each column the FabI containing fractions werepooled, concentrated, and checked for purity and biological activity.

[0200] Cloning/Expression Haemophilus influenzae FabI

[0201] The FabI gene was PCR amplified from Haemophilus influenzae (QI)genomic DNA. Oligonucleotide primers were designed with uniquerestriction sites at both the N′ and C′ terminal ends of the gene toallow efficient sub-cloning into the expression vector pPROLar. FORWARDPRIMER KpnI 5′GCGGTACCCATGCGCTTGGTTTTCTTAGAAATATTG′3 REVERSE PRIMER NotI5′GCGGCCGCTTATTCTTCGCCTAATTCGCCCATTGC′3

[0202] PCR amplification was performed using Pfu Turbo DNA polymerase asper the instructions of the manufacturer (Stratagene). The followingcycling conditions were used: 95° C. for 3 minutes followed by 30 cyclesof 94° C. 1 minute, 55° C. 1 minute and 72° C. 3 minutes. A finalextension at 72° C. for 5 minutes was carried out. PCR products ofexpected size for Haemophilus influenzae FabI were cloned into the PCRcloning vector TOPO TA 2.1 as per instructions of the manufacturer(Invitrogen). The fidelity of the presumptive PCR amplified Haemophilusinfluenzae FabI gene was confirmed by DNA sequencing on both strandsusing an ABI 377 Automative DNA Sequencer (Applied Biosystems). pPROLarwas digested with KpnI and NotI restriction endonucleases usingconditions as recommended by the supplier (New England Biolabs).Purification of the linear plasmid, was achieved using agarose gelpurification and the Qia-quick gel purification kit as per the protocolsupplied by the manufacturer (Qiagen). The Haemophilus influenzae FabIgene was excised from TOPO TA 2.1 by KpnI and NotI restrictionendonuclease digestion and purified as above. Subsequent fragment/vectorligations were carried out using T4 DNA ligase, using conditionssupplied by the manufacturer (Promega).

[0203] Transformations into E. coli TOP 10 competent cells wereperformed using the protocol as supplied by the manufacturer(Invitrogen). Verification of the resultant clones was carried out usingcolony PCR and restriction endonuclease digestion. Positive clones werethen transformed into the expression strain E. coli DH5.PRO, whichexpresses AraC in addition to the lac repressor.

[0204] Subsequent clones were then evaluated for expression atsmall-scale using the conditions as recommended by the manufacturer(Clontech). Expression analysis showed over-expressed protein bands ofcorrect size for Haemophilus influenzae FabI clearly visible by SDSPAGE. Protein identity was further confirmed by peptide massfingerprinting. Further analysis by N-terminal Amino Acid sequencing ofthe purified protein showed that the N-terminus starts 35 residuesdownstream of the presumptive initiation codon. DNA sequence analysisalso highlighted the presence of a ribosome binding site upstream andcorrectly spaced from the new initiation codon. These findings matchperfectly with E. coli FabI and the protein is also now a similar sizeto other FabIs. The over-expression construct has managed to use thecorrect ribosome binding site and start at the correct ATG to give thecorrect protein.

[0205] Purification of H. influenzae FabI

[0206] One liter of cells containing the H. influenzae FabI expressionconstruct were grown to an OD600 of 0.6. Expression was induced asdescribed above and the cells were grown for a further 3 h and thenharvested. The cell pellet was re-suspended in 10 ml 50 mM Tris pH 7.5,1 mM PMSF, 1 mM benzamidine, 1 mM DTT (buffer A) and lysed bysonication. Cell debris was removed by centrifugation. The supernatantwas loaded onto a Hi-load Q (16/10) column (Pharmacia) equilibrated inbuffer A. Protein was eluted over a 200 mL gradient of 0-100% buffer B,where buffer B is buffer A+1 M KCl. Fractions containing FabI wereidentified by SDS PAGE and by their FabI activity and pooled.

[0207] 1.5 M ammonium sulfate was added to the pooled fractions andthese were then loaded onto a Hi-load phenyl sepharose (16/10) column(Pharmacia) equilibrated in 50 mM Tris pH 7.5, 1 mM PMSF, 1 mMbenzamidine, 1 mM DTT, 1.5 M ammonium sulfate. Proteins were eluted witha gradient of ammonium sulfate (1.5 to 0 M) over 200 mL. Fractionscontaining FabI were identified as above and pooled. The pooledfractions were buffer exchanged into 100 mM Tris, pH 7.5, 2 mM DTT andglycerol was then added to 50%. The protein was stored at −20° C. Theidentity of the protein was confirmed by N-terminal sequencing and MALDImass spectrometry.

[0208] Cloning of E. coli FabI:

[0209] A PCR fragment of correct size for E. coli FabI was PCR amplifiedfrom E. coli chromosomal DNA, subcloned into the TOPO TA cloning vector,and verified by colony PCR+restriction endonuclease analysis. Thepresumptive E. coli FabI PCR fragment was subcloned into the expressionvector pBluePet. The FabI clone was transformed into E. coli strainBL21(DE3). Small Scale expression studies show an over-expressed proteinband of correct molecular weight (−28 Kda) for E. coli FabI clearlyvisible following Coomassie staining of SDS PAGE gels. DNA sequencing ofthe E. coli FabI expression constructs illustrated that no errors wereapparent. N′ terminal amino acid sequencing has confirmed theover-expressed protein band to be E. coli FabI.

[0210] Purification of E. coli FabI

[0211]E. coli FabI was expressed as soluble protein to 15% of total cellprotein, 120 g cells being recovered from 3L fermentation in shakeflasks in modified terrific broth. The cells were lysed and the samplecentrifuged. The resulting supernatant was filtered and purified usingthree consecutive chromatography columns: ion-exchange (Sourse 15Q),dye-affinity (blue sepharose), and size exclusion (superose 12). Aftereach column the FabI containing fractions were pooled, concentrated andchecked for purity and biological activity.

[0212]S aureus FabI Enzyme Inhibition Assay (NADH):

[0213] Assays were carried out in half-area, 96-well microtitre plates.Compounds were evaluated in 50-uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-[2-acetamido]-2-iminodiacetic acid), 4 % glycerol,0.25 mM crotonoyl CoA, 1 mM NADH, and an appropriate dilution of S.aureus FabI. Inhibitors were typically varied over the range of 0.01-10uM. The consumption of NADH was monitored for 20 minutes at 30° C. byfollowing the change in absorbance at 340 nm. Initial velocities wereestimated from an exponential fit of the non-linear progress curvesrepresented by the slope of the tangent at t=0 min. IC₅₀'s wereestimated from a fit of the initial velocities to a standard,4-parameter model and are typically reported as the mean ±S.D. ofduplicate determinations. Triclosan, a commercial antibacterial agentand inhibitor of FabI, is currently included in all assays as a positivecontrol. Compounds of this invention have IC₅₀'s from about 5.0micromolar to about 0.05 micromolar.

[0214]S aureus FabI Enzyme Inhibition Assay (NADPH):

[0215] Assays were carried out in half-area, 96-well microtitre plates.Compounds were evaluated in 150-uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-[2-acetamido]-2-iminodiacetic acid), 4% glycerol,0.25 mM crotonoyl CoA, 50 uM NADPH, and an appropriate dilution of S.aureus FabI. Inhibitors were typically varied over the range of 0.01-10uM. The consumption of NADPH was monitored for 20 minutes at 30° C. byfollowing the change in absorbance at 340 nm. Initial velocities wereestimated from an exponential fit of the non-linear progress curvesrepresented by the slope of the tangent at t=0 min. IC₅₀'s wereestimated from a fit of the initial velocities to a standard,4-parameter model and are typically reported as the mean ±S.D. ofduplicate determinations. Triclosan, a commercial antibacterial agentand inhibitor of FabI, is currently included in all assays as a positivecontrol. H. influenzae FabI Enzyme Inhibition Assay:

[0216] Assays are carried out in half-area, 96-well microtiter plates.Compounds are evaluated in 150-uL assay mixtures containing 100 mM MES,51 mM diethanolamine, 51 mM triethanolamine, pH 6.5(MES=2-(N-morpholino)ethanesulfonic acid), 4% glycerol, 25 uMcrotonoyl-ACP, 50 uM NADH, and an appropriate dilution of H. influenzaeFabI (approximately 20 nM). Inhibitors are typically varied over therange of 0.01-10 uM. The consumption of NADH is monitored for 20 minutesat 30° C. by following the change in absorbance at 340 nm. Initialvelocities are estimated from an exponential fit of the non-linearprogress curves. IC50's are estimated from a fit of the initialvelocities to a standard, 4-parameter model, and are typically reportedas the mean ±S.D. of duplicate determinations. The apparent Ki iscalculated assuming the inhibition is competitive with crotonoyl-ACP. Aproprietary lead compound is currently included in all assays as apositive control.

[0217]E. coli FabI Enzyme Inhibition Assay:

[0218] Assays were carried out in half-area, 96-well microtitre plates.Compounds were evaluated in 150-uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-[2-acetamido]-2-iminodiacetic acid), 4% glycerol,0.25 mM crotonoyl CoA, 50 uM NADH, and an appropriate dilution of E.coli FabI. Inhibitors were typically varied over the range of 0.01-10uM. The consumption of NADH was monitored for 20 minutes at 30° C. byfollowing the change in absorbance at 340 nm. Initial velocities wereestimated from an exponential fit of the non-linear progress curvesrepresented by the slope of the tangent at t=0 min. IC₅₀'s wereestimated from a fit of the initial velocities to a standard,4-parameter model and are typically reported as the mean ±S.D. ofduplicate determinations. Triclosan, a commercial antibacterial agentand inhibitor of FabI, is currently included in all assays as a positivecontrol. Compounds of this invention have IC₅₀'s from about 100.0micromolar to about 0.05 micromolar.

[0219] Preparation and Purification of Crotonoyl-ACP:

[0220] Reactions contained 5 mg/mL E. coli apo-ACP, 0.8 mM crotonoyl-CoA(Fluka), 10 mM MgCl₂, and 30 uM S. pneumoniae ACP synthase in 50 mMNaHEPES, pH 7.5. The mixture was gently mixed on a magnetic stirrer at23° C. for 2 hr, and the reaction was terminated by the addition of 15mM EDTA. The reaction mixture was filtered through a 0.2 micron filter(Millipore) and applied to a MonoQ column (Pharmacia) equilibrated with20 mM Tris-Cl, pH 7.5. The column was washed with buffer until allnon-adherent material was removed (as observed by UV detection), and thecrotonoyl-ACP was eluted with a linear gradient of 0 to 400 mM NaCl.

[0221]S. aureus FabI Enzyme Inhibition Assay Using Crotonoyl-ACP:

[0222] Assays are carried out in half-area, 96-well microtitre plates.Compounds are evaluated in 150 uL assay mixtures containing 100 mMNaADA, pH 6.5 (ADA=N-(2-acetamido)-2-iminodiacetic acid), 4% glycerol,25 uM crotonoyl-ACP, 50 uM NADPH, and an appropriate dilution of S.aureus Fab I (approximately 20 nM). Inhibitors are typically varied overthe range of 0.01-10 uM. The consumption of NADPH is monitored for 20minutes at 30° C. by following the change in absorbance at 340 nm.Initial velocities are estimated from a linear fit of the progresscurves. IC50's are estimated from a fit of the initial velocities to astandard, 4-parameter model (Equation 1) and are typically reported asthe mean ±S.D. of duplicate determinations. Compounds of this inventionin this assay have IC₅₀'s from about 100.0 micromolar to about 0.04micromolar. The apparent Ki is calculated from Equation 2 assuming theinhibition is competitve with crotonoyl-ACP.

v=Range/(1+[I]/IC50)s+Background   Equation 1:

Ki(app)=IC50/(1+[S]/Ks)  Equation 2:

[0223] Antimicrobial Activity Assay:

[0224] Whole-cell antimicrobial activity was determined by brothmicrodilution using the National Committee for Clinical LaboratoryStandards (NCCLS) recommended procedure, Document M7-A4, “Methods forDilution Susceptibility Tests for Bacteria that Grow Aerobically”. Thecompound was tested in serial two-fold dilutions ranging from 0.06 to 64mcg/mL. Test organisms were selected from the following laboratorystrains: Staphylococcus aureus Oxford, Staphylococcus aureus WCUH29,Streptococcus pneumoniae ERY2, Streptococcus pneumoniae 1629,Streptococcus pneumoniae N 1387, Enterococcus faecalis 1, Enterococcusfaecalis 7, Haemophilus influenzae Q1, Haemophilus influenzae NEMCl,Moraxella Catarrhalis 1502, Escherichia coli 7623 AcrABEFD+, Escherichiacoli 120 AcrA B-, Escherichia coli MG1655, Escherichia coli MG1658. Theminimum inhibitory concentration (MIC) was determined as the lowestconcentration of compound that inhibited visible growth. A mirror readerwas used to assist in determining the MIC endpoint.

[0225] One skilled in the art would consider any compound with a MIC ofless than 256 μg/mL to be a potential lead compound. Preferably, thecompounds used in the antimicrobial assays of the present invention havea MIC value of less than 128 μg/mL. Most preferably, said compounds havea MIC value of less than 64 μg/mL.

[0226] The examples which follow are intended in no way to limit thescope of this invention, but are provided to illustrate how to make anduse the compounds of this invention. Many other embodiments will bereadily apparent to those skilled in the art.

EXAMPLES General

[0227] Proton nuclear magnetic resonance (¹H NMR) spectra were recordedat either 300 or 400 MHz, and chemical shifts are reported in parts permillion (8) downfield from the internal standard tetramethylsilane(TMS). Abbreviations for NMR data are as follows: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet oftriplets, app=apparent, br=broad. J indicates the NMR coupling constantmeasured in Hertz. CDCl₃ is deuteriochloroform, DMSO-d₆ ishexadeuteriodimethylsulfoxide, and CD₃OD is tetradeuteriomethanol. Massspectra were obtained using electrospray (ES) ionization techniques.Elemental analyses were performed by Quantitative Technologies Inc.,Whitehouse, N.J. Melting points were obtained on a Thomas-Hoover meltingpoint apparatus and are uncorrected. All temperatures are reported indegrees Celsius. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254thin layer plates were used for thin layer chromatography. Flashchromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh)silica gel. Analytical HPLC was performed on Beckman chromatographysystems. Preparative HPLC was performed using Gilson chromatographysystems. ODS refers to an octadecylsilyl derivatized silica gelchromatographic support. YMC ODS-AQ® is an ODS chromatographic supportand is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is apolymeric (styrene-divinylbenzene) chromatographic support, and is aregistered trademark of Hamilton Co., Reno, Nev. Celite® is a filter aidcomposed of acid-washed diatomaceous silica, and is a registeredtrademark of Manville Corp., Denver, Colo..

Preparation 1

[0228] Preparation of (E)-3-(6-aminopyridin-3-yl)acrylic Acid (Method A)

[0229] a) Benzyl (E)-3-(6-aminopyridin-3-yl)acrylate

[0230] A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole),benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)₂ (0.31 g, 1.4 mmole),tri-ortho-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine(3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at refluxovernight. The dark mixture was filtered through celite®, and thefiltrate was concentrated. Flash chromatography on silica gel (3%MeOH/CH₂Cl₂) gave the title compound (1.3 g, 39%): MS (ES) m/e 255(M+H)⁺.

[0231] b) (E)-3-(6-Aminopyridin-3-yl)acrylic Acid

[0232] A solution of benzyl (E)-3-(6-arninopyridin-3-yl)acrylate (1.3 g,5.1 mmole) and 1.0 N NaOH (10 mL, 10 mmole) in MeOH was heated at refluxovernight. The solution was concentrated in vacuo, and the residue wasdissolved in H₂O. The pH was adjusted to 6 with dilute HCl, and thesolid precipitate was collected by suction filtration and dried to givethe title compound (0.6 g, 72%) as a white solid: MS (ES) m/e 165(M+H)⁺.

Preparation 2

[0233] Preparation of (E)-3-(6-aminopyridin-3-yl)acrylic Acid (Method B)

[0234] a) (E)-3-(6-Aminopyridin-3-yl)acrylic Acid

[0235] Acrylic acid (23 mL, 0.33 mole) was added carefully to a solutionof 2-amino-5-bromopyridine (25.92 g, 0.15 mole) and Na₂CO₃ (55.64 g,0.53 mole) in H₂O (600 mL). PdCl₂ (0.53 g, 0.003 mole) was then added,and the mixture was heated at reflux. After 24 hr, the reaction wascooled to RT and filtered, and the filtrate was adjusted to pH 6 withaqueous HCl. Additional H₂O (0.5 L) was added to improve mixing, and themixture was stirred for 1 hr. The pH was readjusted to 6, then the solidwas collected by suction filtration. The filter pad was washedsequentially with H₂O (2×0.5 L), cold absolute EtOH (100 mL), and Et₂O(2×250 mL). Drying in high vacuum at elevated temperature gave the titlecompound (15.38 g, 62%) as a tan solid: 1H NMR (300 MHz, DMSO-d₆) δ 8.11(d, J=2.0 Hz, 1 H), 7.75 (dd, J=8.7, 2.0 Hz, 1 H), 7.43 (d, J=15.8 Hz, 1H), 6.53 (s, 2 H), 6.45 (d, J=8.7 Hz, 1 H), 6.22 (d, J=15.8 Hz, 1 H); MS(ES) m/e 165 (M+H)⁺.

Preparation 3

[0236] Preparation of (E)-3-(2-aminopyrimidin-5-yl)acrylic Acid

[0237] a) Benzyl (E)-3-(2-aminopyrimidin-5-yl)acrylate

[0238] According to the procedure of Preparation 1 (a), exceptsubstituting 5-bromo-2-aminopyrimidine (1.95 g, 11.2 mmole) for2-amino-5-bromopyridine, the title compound (2.25 g, 79%) was preparedas a light orange solid: MS (ES) m/e 256 (M+H)⁺.

[0239] b) (E)-3-(2-Aminopyrimidin-5-yl)acrylic Acid

[0240] According to the procedure of Preparation 1 (b), exceptsubstituting benzyl (E)-3-(2-aminopyrimidin-5-yl)acrylate (2.93 g, 11.5mmole) for benzyl (E)-3-(6-aminopyridin-3-yl)acrylate, the titlecompound (1.71 g, 90%) was prepared as an off-white solid: MS (ES) m/e166 (M+H)⁺.

Preparation 4

[0241] Preparation of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one

[0242] a) 2-Amino-3-(hydroxymethyl)pyridine

[0243] Solid 2-aminonicotinic acid (199 g, 1.44 mole) was added inportions over 4 hr to 1.0 M LiAlH₄ in THF (3 L, 3 mole) with stirringunder Argon. An ice-bath was applied to control the temperature below30° C. After the addition was complete, the reaction was heated atreflux for 16 hr, then was cooled to 0° C. and carefully quenched bysequential addition of H₂O (120 mL), 15% NaOH in H₂O (120 mL), and H₂O(350 mL). The resulting thick suspension was stirred for 1 hr, then wasfiltered through a pad of celite®. The filter pad was rinsed with THF (1L), and the filtrate was concentrated to dryness to give the titlecompound (156 g, 87%) as a pale yellow waxy solid: MS (ES) m/e 125.1(M+H)³⁰ ; ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (dd, 1 H), 7.37 (m, 1 H),6.53 (dd, 1 H), 5.65 (br s,2 H), 5.16 (t, 1 H), 4.34 (d, J=4.6 Hz, 2 H).

[0244] b) 2-Amino-5-bromo-3-(hydroxymethyl)pyridine Hydrobromide

[0245] To a stirred solution of 2-amino-3-(hydroxymethyl)pyridine (156g, 1.257 mole) in HOAc (2.5 L) at ambient temperature was added bromine(64.1 mL, 1.257 mole) dropwise over 1 hr. A suspension began to formduring the addition. An exotherm to 36° C. was controlled with an icebath. After the addition, the reaction mixture was stirred at ambienttemperature overnight. The yellow precipitate was filtered, washed withether and air-dried to give the title compound (289 g, 81%): MS (ES) m/e203.2 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆, free base) δ 7.89 (d, J=2.3 Hz,1 H), 7.52 (s, 1 H), 5.92 (br s, 2 H), 5.29 (br s, 1 H), 4.30 (s, 2 H).

[0246] c) 2-Amino-5-bromo-3-(bromomethyl)pyridine Hydrobromide

[0247] A suspension of 2-amino-5-bromo-3-(hydroxymethyl)pyridinehydrobromide (289 g, 1.02 mole) in 48% aqueous HBr (2.9 L) was heated atreflux for 12 hrs. Complete solution occurred during heating. Thereaction mixture was cooled and a crystalline precipitate formed. Thiswas filtered and washed with ethyl acetate and air dried to give thetitle compound (305 g, 86%).

[0248] d) Methyl(±)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate

[0249] To a solution of dimethyl malonate (224 g, 1.7 mole) in DMF (2 L)and THF (2 L) stirred under argon and chilled to 3° C. with anice-acetone bath was added NaH (60% Nujol dispersion, 69.2 g, 1.7 mole)in portions over 1.5 hr. The anion solution was stirred for 15 min atca. 5° C., then 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide(200 g, 0.56 mole) was added in portions over 15 min. The reactionmixture was allowed to warm to ambient temperature during overnightstirring and then was heated to 80° C. for 2 hr. The reaction was thencooled and filtered and the precipitate was washed with ethyl acetate.This solid was then vigorously stirred in 2 L water for 15 min and againfiltered and air-dried to give the title compound (113 g, 71%): MS (ES)m/e 286 (M+H)⁺.

[0250] e) 6-Bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one

[0251] To a suspension of methyl(±)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate(170 g, 0.596 mole) in CH₃OH (10 L) was added 1.0 M NaOH (2.5 L). Thereaction mixture was stirred and heated at reflux for 5 hrs and thencooled to ambient temperature. The suspension was acidified with 1.0 MHCl (3.0 L) and then was stirred and heated at reflux overnight. Thereaction slurry was cooled and filtered and the solid was washed withwater and vacuum dried to give the title compound (122 g of the hydrate,90%) as an off-white solid, HPLC purity, 94%: MS (ES) m/e 228 (M+H)⁺.

Preparation 5

[0252] Preparation of6-bromo-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

[0253] a) 2-Amino-5-bromo-3-(methylaminomethyl)pyridine

[0254] A solution of 2-amino-5-bromo-3-(hydroxymethyl)pyridine (5.00 g,24.6 mmole), from Preparation 4 (b), in 48% aqueous HBr (50 mL) washeated at reflux for 12 hrs. The reaction was concentrated and toluenewas used to azeotrope the residual H₂O. The resulting light brown solidwas placed under high vacuum overnight and used directly.

[0255] A solution of the 2-amino-3-(bromomethyl)-5-bromopyridinehydrobromide salt (prepared above) in 40% aqueous methylamine (50 mL)and THF (50 mL) was stirred at RT overnight in a pressure bottle. Thereaction solution was concentrated and extracted with EtOAc (2×100 mL).The combined organic phases were washed with H₂O, dried over Na₂SO₄ andconcentrated. Purification on silica gel afforded the title compound(4.25 g, 80%) as a yellow oil: MS (ES) m/e 217 (M+H)⁺.

[0256] b) 6-Bromo-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

[0257] To a solution of 2-amino-5-bromo-3-(methylaminomethyl)pyridine(2.0 g, 9.3 mmole) in dichloroethane (50 mL) was added1,1′-carbonyldiimidazole (1.9 g, 11.5 mmole). The reaction was heated at50° C. overnight and concentrated. The residue was purified on silicagel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) to give the title compound(1.72 g, 77%) as an off-white solid: MS (ES) m/e 243 (M+H)⁺.

Preparation 6

[0258] Preparation of (E)-3-(3H-imidazo[4.5-b]pyridin-6-yl)acrylic Acid

[0259] a) 5-Bromo-2,3-diaminopyridine

[0260] To a suspension of 2-amino-5-bromo-3-nitropyridine (2.0 g, 9.17mmole) in absolute EtOH (50 mL) was added SnCl₂ hydrate (9.3 g, 41.3mmole), then the mixture was heated to reflux. After 3 hr the mixturewas cooled to RT and concentrated. The residue was taken up in 2.0 MNaOH and extracted with EtOAc (3×). The combined organic layers weredried (MgSO₄), filtered, and concentrated to give the title compound(1.69 g, 98%) which was sufficiently pure for use in the next step: MS(ES) m/e 188/190 (M+H)⁺.

[0261] b) 6-Bromo-3H-imidazo[4,5-b]pyridine

[0262] 5-Bromo-2,3-diaminopyridine (1.69 g, 8.99 mmole) was taken up in96% formic acid (50 ML) and heated to reflux. After 18 hr the mixturewas cooled to RT and concentrated. The residue was taken up in H₂O andthe pH was adjusted to 7 with 2.0 M NaOH. The title compound (1.54 g,87%) was collected as a solid by filtration, washed with H₂O, and driedin vacuo: MS (ES) m/e 198/200 (M+H)⁺.

[0263] c) 6-Bromo-4-trityl-3H-imidazo[4,5-b]pyridine

[0264] To a suspension of 6-bromo-3H-imidazo[4,5-b]pyridine (1.2 g, 6.06mmole) in CH₂Cl₂ (30 mL) was added Et₃N (1.3 mL, 9.09 mmole) then tritylchloride (2.03 g, 7.27 mmole) at RT. After 72 hr the mixture was washedwith H₂O (2×) and brine, then was dried (MgSO₄), filtered, andconcentrated under reduced pressure to afford the title compound. Thiswas used directly in the next step.

[0265] d) Benzyl (E)-3-(4-trityl-3H-imidazo[4,5-b]pyridin-6-yl)acrylate

[0266] A solution of 6-bromo-4-trityl-3H-imidazo[4,5-b]pyridine (fromstep a) (6.06 mmole), benzyl acrylate (1.18 g, 7.27 mmole), Pd(OAc)₂ (67mg, 0.30 mmole), P(o-tolyl)₃ (183 mg, 0.6 mmole), and (i-Pr)₂NEt (2.64mL, 15.15 mmole) in propionitrile (30 mL) was degassed (3×N₂/vacuum)then heated to reflux. After 4 hr the mixture was cooled to RT andconcentrated. Flash chromatography on silica gel (30% EtOAc/hexanes)gave the title compound (1.75 g, 55% over 2 steps) as an off-white foam:¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.0 Hz, 1 H), 8.19 (d, J=2.0 Hz, 1H), 8.06 (s, 1 H), 7.77 (d, J=16.0 Hz, 1 H), 7.42-7.11 (m, 20 H), 6.48(d, J=16.0 Hz, 1 H), 5.25 (s, 2 H).

[0267] d) (E)-3-(3H-Imidazo[4,5-b]pyridin-6-yl)acrylic Acid

[0268] Benzyl (E)-3-(4-trityl-3H-imidazo[4,5-b]pyridin-6-yl)acrylate(1.75 g, 3.35 mmole) was dissolved in 4 N HCl in dioxane (20 mL). After1 hr the mixture was concentrated. The residue was taken up in 1:1MeOH/H₂O (15 mL). 2.0 N NaOH (15 mL, 15 mmole) was added and the mixturewas heated to reflux. After 18 hr the mixture was cooled to RT andconcentrated to approximately ⅓ volume. The mixture was adjusted to pH 4using 10% HCl. The solid was collected by filtration, washed with H₂O,and dried in vacuo to give the title compound (329 mg, 52% over 2 steps)as a white solid: ¹H NMR (400 MHz, d⁶-DMSO) δ 9.10 (s, 1 H), 8.94 (s, 1H), 8.84 (s, 1 H), 8.20 (d, J=16.0 Hz, 1 H), 7.10 (d, J=16.0 Hz, 1 H).

Preparation 7

[0269] Preparation of(E)-3-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl)acrylic Acid

[0270] a) 3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazine

[0271] To a suspension of 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.0 g,13.3 mmole) in dry THF (40 mL) was added a solution of LiAlH₄ in THF(1.0 M, 26.6 mL, 26.6 mmole) slowly at 0° C. After 1 hr the mixture wasquenched with 2.0 M NaOH until a solid formed. The mixture was dried(MgSO₄), filtered, and concentrated under reduced pressure to give thetitle compound (1.44 g, 79%) as a white solid which was sufficientlypure for use in the next step: MS (ES) m/e 137 (M+H)⁺.

[0272] b)4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine

[0273] To a solution of 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (1.44g, 10.6 mmole) and di-tert-butyl dicarbonate (2.78 g, 12.7 mmole) in dryTHF (50 mL) was added a solution of LiHMDS in THF (1.0 M, 12.7 mL, 12.7mmole) dropwise at 0° C. After 30 min the mixture was quenched withsaturated NH₄Cl and extracted with EtOAc (3×). The combined organiclayers were dried (MgSO₄), filtered, and concentrated. Flashchromatography on silica gel (40% EtOAc/hexanes) gave the title compound(2.0 g, 80%) as a clear oil: MS (ES) m/e 237 (M+H)⁺.

[0274] c)4-(tert-Butoxycarbonyl)-7-bromo-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine

[0275] To a solution of4-(tert-butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (2.0 g,8.46 mmole) in MeOH (40 mL) was added Br₂ (0.53 mL, 10.2 mmole) dropwiseat 0° C. After 1 hr the mixture was concentrated. The residue was takenup in 1:1 Et₂O/hexanes and filtered. The filtrate was concentrated underreduced pressure to give the title compound (1.27 g, 48%) as an oilwhich solidified under vacuum: ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1 H),7.33 (s, 1 H), 4.25 (m, 2 H), 3.92 (m, 2 H), 1.54 (s, 9 H).

[0276] d)(E)-3-[4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl]acrylicAcid

[0277] A solution of4-(tert-butoxycarbonyl)-7-bromo-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine(1.27 g, 4.03 mmole), benzyl acrylate (785 mg, 4.84 mmole), Pd(OAc)₂ (45mg, 0.20 mmole), P(o-tolyl)3 (122 mg, 0.4 mmole), and (i-Pr)₂NEt (1.76mL, 10.1 mmole) in propionitrile (20 mL) was degassed (3×N₂/vacuum) thenheated to reflux. After 18 hr the mixture was cooled to RT andconcentrated. Flash chromatography on silica gel (25% EtOAc/hexanes)gave the title compound (1.17 g, 73%) as a yellow oil: MS (ES) m/e 397(M+H)⁺.

[0278] e) (E)-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylicAcid

[0279](E)-3-[4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl]acrylicacid (1.17 g, 2.95 mmole) was dissolved in 4 N HCl in dioxane (15 mL).After 72 hr the mixture was concentrated. The residue was taken up in1:1 MeOH/H₂O (20 mL). 1.0 N LiOH (15 mL, 15 mmole) was added and themixture was heated to reflux. After 18 hr the mixture was cooled to RTand concentrated to approximately ⅓ volume. The mixture was adjusted topH 6 using 10% HCl. The solid was collected by filtration, washed withH₂O and dried in vacuo to give the title compound (315 mg, 52% over 2steps): MS (ES) m/e 207 (M+H)⁺.

Preparation 8

[0280] Preparation of 5-bromo-2,2′-dipyridylamine

[0281] To a stirred solution of 2,5-dibromopyridine (2.4 g, 10.1 mmole)in dry toluene (75 mL) were added 2-aminopyridine (1.0 g, 10.6 mmole),tris(dibenzylideneacetone)dipalladium(0) (183 mg, 0.2 mmole),1,3-bis(diphenylphosphino)propane (165 mg, 0.4 mmole) and sodiumtert-butoxide (1.35 g, 14 mmole). The reaction was purged with Ar thenheated with stirring at 70° C. After 4 h the reaction was cooled to RT,taken up in Et₂O (200 mL), washed with brine, dried (MgSO₄) andconcentrated to dryness. The remaining residue was purified by flashchromatography on silica gel (0.5% (5% NH₄OH/MeOH)/CHCl₃), trituratedwith hexane and dried under vacuum to give the title product (1.31 g,52%) as a pale yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 9.88 (s, 1 H),8.31 (s, 1 H), 8.23 (d, J=4.8 Hz, 1 H), 7.83 (m, 2 H), 7.67 (t, 1 H),7.62 (d, J=8.4 Hz, 1 H), 6.90 (t, 1 H); MS (ES) m/e 250.0 (M+H)⁺.

Preparation 9

[0282] Preparation of 1-methyl-2-(methylaminomethyl)-1H-indole

[0283] a) Ethyl 1-methyl-1H-indole-2-carboxylate

[0284] NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) waswashed with hexanes, then was suspended in dry DMF (530 mL). Solid ethylindole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over5-10 min, allowing gas evolution to subside between additions. When theaddition was complete, the yellow mixture was stirred for 15 min, thenmethyl iodide (42 mL, 668.3 mmole) was added all at once. The reactionwas exothermic, and the internal temperature rose to 40-45° C. After 1hr, the reaction was quenched with 10% NH₄Cl (100 mL) and concentratedon the rotavap (high vacuum). The residue was partitioned betweenEt₂O(500 mL) and H₂O (100 mL), and the layers were separated. The Et₂Olayer was washed with H₂O (100 mL), dried (MgSO₄), and concentrated toleave the title compound (27.10 g, quantitative) as a light yellowsolid. This was used without further purification: TLC (10%EtOAc/hexanes) Rf=0.39.

[0285] b) N,1-Dimethyl-1H-indole-2-carboxamide

[0286] A suspension of ethyl 1-methyl-1H-indole-2-carboxylate (27.10 g,133.34 mmole) in 40% aqueous CH₃NH₂ (300 mL) and MeOH (30 mL) wasstirred at RT. A solid tended to gradually creep up the walls of theflask, and was washed down periodically with MeOH. The flask was tightlystoppered to keep the material inside the flask. As the reactionproceeded, the solid dissolved, but eventually the product began toprecipitate. The reaction was stirred at RT for 5 days, then wasconcentrated to remove approximately 200 mL of the solvent. Theremaining residue was diluted with H₂O (300 mL), and the solid wascollected by suction filtration and washed with H₂O. Drying at 50-60° C.in high vacuum left the title compound (23.45 g, 93%) as a faintlyyellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.63 (d, J=8.0 Hz, 1 H), 7.27-7.43 (m, 2 H), 7.10 -7.20 (m, 1 H), 6.80 (s, 1 H), 6.10-6.30 (m, 1 H),4.06 (s, 3 H), 3.01 (d, J=4.9 Hz, 3 H).

[0287] c) 1-Methyl-2-(methylaminomethyl)-1H-indole

[0288] A 3-liter 3-necked roundbottom flask equipped with overheadstirring was charged with N,1-dimethyl-1H-indole-2-carboxamide (23.45 g,124.58 mmole) and anhydrous THF (170 mL). The solution was stirred whilea solution of LiAlH₄ in THF (1.0 M, 250 mL, 250 mmole) was added viasyringe. Gas was evolved during the addition of the first 50 mL ofLiAlH₄ solution. When the addition was complete, the resulting lightyellow solution was heated at gentle reflux. After 23 hr, the reactionwas cooled in ice and quenched by the sequential dropwise addition ofH₂O (9.5 mL), 15% NaOH (9.5 mL), and H₂O (28.5 mL). The mixture wasstirred for 15 min, then was filtered through celite®, and the filterpad was washed thoroughly with THF. The filtrate was concentrated andthe residue was flash chromatographed on silica gel (10% MeOH/CHCl₃containing 0.5% conc. NH₄OH). The title compound (20.17 g, 93%) wasobtained as a light yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J=7.8Hz, 1 H), 7.02 -7.35 (m, 3 H), 6.38 (s, 1 H), 3.88 (s, 2 H), 3.75 (s,3H),2.49(s,3H).

Preparation 10

[0289] Preparation of 1-methyl-3-(methylaminomethyl)-1H-indole (MethodA)

[0290] a) Methyl 1-methyl-1H-indole-3-carboxylate

[0291] NaH (60% dispersion in mineral oil, 8.56 g, 214.0 mmole) wasadded portionwise, allowing for gas evolution, to a solution of methyl1H-indole-3-carboxylate (25.00 g, 142.7 mmole) in DMF (350 mL) at 0° C.When the NaH addition was complete, methyl iodide (44.4 mL, 713.5 mmole)was added at 0° C. The reaction was stirred at 0° C. for 15 minutes thenat RT overnight. The reaction was diluted with water and extracted withethyl acetate. The combined extracts were dried over K₂CO₃ andconcentrated to afford the title compound (26.00 g, 96%) as an orangesolid: MS (ES) m/e 190 (M+H)⁺.

[0292] b) N,1-Dimethyl-1H-indole-3-carboxamide

[0293] A suspension of methyl 1-methyl-1H-indole-3-carboxylate (4.30 g,22.74 mmole) in 40% aqueous CH₃NH₂ (400 mL) was stirred at RT. The flaskwas tightly stoppered to keep the material inside the flask. As thereaction proceeded the product began to precipitate. The reaction wasstirred at RT for 3 days, then was concentrated to remove approximately200 mL of the solvent. The remaining residue was diluted with H₂O (500mL), and the solid was collected by suction filtration and washed withH₂O. Flash chromatography on silica gel (ethyl acetate) gave the titlecompound (2.4 g, 56%) as a white solid: MS (ES) m/e 189 (M+H)⁺.

[0294] c) 1-Methyl-3-(methylaminomethyl)-1H-indole

[0295] A solution of LiAlH₄ in THF (1.0 M, 5.20 mL, 5.2 mmole) wasslowly added via syringe to a solution ofN,1-dimethyl-1H-indole-3-carboxamide (0.50 g, 2.6 mmole) in anhydrousTHF (15 mL). Gas was evolved during the addition of the first 2 mL ofLiAlH₄ solution. When the addition was complete, the resulting lightyellow solution was heated at gentle reflux. After 23 hr, the reactionwas cooled in ice and quenched by the sequential dropwise addition ofH₂O (0.5 mL), 1.0 N NaOH (0.5 mL), and H₂O (0.5 mL). The mixture wasstirred for 15 min, then was filtered through celite®, and the filterpad was washed thoroughly with THF. The filtrate was concentrated andthe residue was flash chromatographed on silica gel (10% MeOH/CHCl₃containing 0.5% conc. NH₄OH) to afford the title compound (0.30 g, 67%)as a light yellow oil: MS (ES) m/e 175 (M+H)⁺.

Preparation 11

[0296] Preparation of 1-methyl-3-(methylaminomethyl)-1H-indole (MethodB)

[0297] To a solution of 1-methylindole-3-carboxaldehyde (10.0 g, 62.8mmole) in MeOH (100 mL) was added a solution of 2.0 M CH₃NH₂ in MeOH(126 mL, 252.0 mmole). The reaction was stirred at RT for 2 hrs, thenwas concentrated to a light yellow oil. This oil was dissolved in EtOH(300 mL), and NaBH₄ (2.38 g, 62.8 mmole) was added. After 2 hrs thereaction was concentrated to a slurry and dissolved in 1.0 N NaOH (75mL). The aqueous solution was extracted with Et₂O (2×200 mL) and thecombined organic fractions were dried over Na₂SO₄ and concentrated.Flash chromatography on silica gel (9:1 CHCl₃/MeOH containing 5% NH₄OH)and drying in high vacuum left the title compound (10.1 g, 92%) as afaintly yellow oil: MS (ES) m/e 175 (M+H)⁺.

Preparation 12

[0298] Preparation of 2-methyl-3-(methylaminomethyl)indole

[0299] To a solution of 2-methylindole-3-carboxaldehyde (10.00 g, 62.84mmole) in MeOH (100 mL) was added 2 M CH₃NH₂ in MeOH (200 mL). Afterstirring for 3 hours at RT, the reaction solution was concentrated to ayellow oil which solidified under vacuum. This solid was dissolved inethanol (350 mL) and NaBH4 (2.38 g, 62.8 mmole) was added. The reactionwas stirred at RT for 6 hours, then was concentrated under vacuum. Theremaining residue was diluted with saturated aqueous Na₂CO₃ (50 mL) andextracted with EtOAc (2×200 mL). The organic phase was separated, washedwith brine, and dried over Na₂SO₄. Flash chromatography on silica gel(9:1 CHCl₃/MeOH containing 5% NH₄OH) and drying under high vacuum gavethe title compound (6.88 g, 63%) as a faintly yellow viscous solid: MS(ES) m/e 175 (M+H)⁺.

Preparation 13

[0300] Preparation of 1,3-dimethyl-2-(methylaminomethyl)-1H-indole

[0301] a) 1,3-Dimethyl-1H-indole

[0302] To a stirred solution of 3-methylindole (15.0 g, 114 mmole) indry DMF (200 mL) was added NaH (60% dispersion in oil, 5.0 g, 125 mmole)in portions. Gas evolution was observed. The mixture was stirred for 30min, then iodomethane (8 mL, 129 mmole) was added in one portion. Thereaction became exothermic and was cooled in an ice bath. After 16 hr atRT, the reaction was concentrated under vacuum and the residue was takenup in ethyl acetate. The solution was washed with H₂O then with brine,dried (MgSO₄), and concentrated to dryness. Purification by short pathdistillation under vacuum (bp 88-92° C., 0.5 mmHg) gave the titlecompound (16.10 g, 97%) as a pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ7.47 (d, J=7:9 Hz, 1 H), 7.35 (d, J=8.2 Hz, 1 H), 7.13 (t, 1 H), 7.06(s, 1 H), 7.00 (t, 1 H), 3.71 (s, 3 H), 2.24 (s, 3 H).

[0303] b) 1,3-Dimethyl-1H-indole-2-carboxaldehyde

[0304] To a stirred solution of phosphorus oxychloride (7.0 mL, 75mmole) in DMF (25 mL) was added dropwise a solution of1,3-dimethylindole (12.0 g, 83 mmole) in dry DMF (6.0 mL). The reactionwas stirred at RT for 2 hr then was poured onto ice. The mixture wasbasified with a solution of NaOH (13.2 g, 330 mmole) in H₂O (44 mL),then was extracted with Et₂O (2×50 mL). The combined organic layers werewashed with brine, dried (MgSO₄), and concentrated under vacuum. Flashchromatography on silica gel (10% ethyl acetate/hexanes) gave the titlecompound (13.03 g, 91%) as an off-white solid: LCMS (ES) m/e 174.2(M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 10.16 (s, 1 H), 7.68 (d, J=8.1 Hz, 1H), 7.42 (t, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 7.15 (t, 1 H), 4.04 (s, 3H), 2.63 (s, 3 H).

[0305] c) 1 ,3-Dimethyl-2-(methylaminomethyl)-1H-indole

[0306] To 1,3-dimethyl-1H-indole-2-carboxaldehyde (13.0 g, 75 mmole) wasadded a solution of 2.0 M methylamine in methanol (150 mL, 300 mmole)and HOAc (4.3 mL, 75 mmole). The solution was stirred at RT for 4 hr,then was cooled to 0° C., and sodium cyanoborohydride (5.0 g, 80 mmole)was added portionwise over 5 min. The reaction was then allowed to warmto RT. After 16 hr, the reaction was concentrated under vacuum and theresidue was taken up in Et₂O. The solution was washed with 1.0 N NaOHthen with brine, dried (Na₂SO₄), and concentrated to dryness. Flashchromatography on silica gel (95:5 CHCl₃/methanol containing 5% NH₄OH)gave the title compound (7.34 g, 52%) as a yellow oil: ¹H NMR (400 MHz,CDCl₃) δ 7.53 (d, J=7.8 Hz, 1 H), 7.26 (d, J=7.8 Hz, 1 H), 7.20 (t, 1H), 7.09 (t, 1 H), 3.88 (s, 2 H), 3.76 (s, 3 H), 2.46 (s, 3 H), 2.32 (s,3 H), 1.36 (br s, 1 H).

Preparation 14

[0307] Preparation of1-methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine

[0308] a) 1-Methyl-1H-pyrrolo[2,3-b]pyridine

[0309] According to the procedure of Preparation 13 (a), exceptsubstituting 7-azaindole (2.28 g, 1.83 mmole) for the 3-methylindole,the title compound (1.4 g, 58%) was prepared as a yellow oil: MS (ES)m/e 133 (M+H)⁺.

[0310] b) 1-Methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde

[0311] According to the procedure of Preparation 13 (b), exceptsubstituting 1-methyl-1H-pyrrolo[2,3-b]pyridine (0.7 g, 5.3 mmole) forthe 1,3-dimethylindole, the title compound (0.4 g, 47%) was prepared asa white solid: MS (ES) m/e 161 (M+H)⁺.

[0312] c) 1-Methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine

[0313] According to the procedure of Preparation 13 (c), exceptsubstituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g,2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the titlecompound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176(M+H)⁺.

Preparation 15

[0314] Preparation of 2-methyl-3-(methylaminomethyl)benzo[b]thiophene

[0315] a) 2-Methylbenzo[b]thiophene-3-carboxaldehyde

[0316] SnCL₄ (20 mL, 67 mmole) was added over 5 min to a stirredsolution of 2-methylbenzo[b]thiophene (5.0 g, 33.7 mmole) in CH₂Cl₂ (75mL) at 0° C. under argon. After 15 minutes, dichloromethyl methyl ether(3.7 mL, 41 mmole) was added. The reaction became a yellowish coloredsuspension. The reaction was allowed to warm to RT and stirred for 16 h,then was poured onto ice water (200 mL). The aqueous mixture wasacidified with 1.0 N HCl (100 mL) and stirred until the suspensiondissolved. The organic phase was separated, dried (MgSO₄), andconcentrated under vacuum. Purification by flash chromatography onsilica gel (10% ethyl acetate/hexane) gave the title compound (5.83 g,98%) as a white crystalline solid: ¹H NMR (400 MHz, CDCl₃) δ 10.38 (s, 1H), 8.61 (d, J=8.1 Hz, 1 H), 7.77 (d, J=8.0Hz, 1 H), 7.48 (t, 1 H), 7.39(t, 1 H), 2.93 (s, 3 H).

[0317] b) 2-Methyl-3-(methylaminomethyl)benzo[b]thiophene

[0318] According to the procedures of Preparation 1, except substituting2-methylbenzo[b]thiophene-3-carboxaldehyde (5.0 g, 28.4 mmole) for1-methylindole-3-carboxaldehyde, the title compound (4.89 g, 90%) wasprepared as an oil which solidified in the freezer: ¹H NMR (400 MHz,CDCl₃) δ 7.78 (d, J=7.9 Hz, 1 H), 7.75 (d, J=7.9 Hz, 1 H), 7.37 (t, 1H), 7.29 (t, 1 H), 3.95 (s, 2 H), 2.60 (s, 3 H), 2.50 (s, 3 H).

Preparation 16

[0319] Preparation of 3-(methylaminomethyl)-1H-indole

[0320] a) 3-(Methylaminomethyl)-1H-indole

[0321] To a solution of indole-3-carboxaldehyde (5.4 g, 34.1 mmole) inMeOH (30 mL) was added a solution of 2.0 M CH₃NH₂ in MeOH (51.3 mL,102.6 mmole). The reaction was stirred at RT overnight, then wasconcentrated to a light yellow oil. This oil was dissolved in EtOH (40mL), and NaBH₄ (1.3 g, 34.1 mmole) was added. After 16 hrs the reactionwas concentrated to a slurry and dissolved in 10% Na₂CO₃(100 mL). Theaqueous solution was extracted with EtOAc (2×200 mL) and the combinedorganic fractions were dried over Na₂SO₄ and concentrated. Drying inhigh vacuum left the title compound (5.2 g, 94%) as a faintly yellowoil: MS (ES) m/e 161 (M+H)⁺.

Preparation 17

[0322] Preparation of 1-benzyl-3-(methylaminomethyl)-1H-indole

[0323] a) 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole

[0324] N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was addedto a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole),from Preparation 16, and triethylamine (5.0 mL, 65.7 mmole) in DMF (100mL) at RT. The reaction was stirred overnight then was concentrated invacuo. The residue was diluted with water and the mixture was extractedwith ethyl acetate. The combined extracts were dried over Na₂SO₄ andconcentrated. Flash chromatography on silica gel (33% ethylacetate/hexanes) gave the title compound (7.0 g, 74%) as an off-whitesolid: MS (ES) m/e 295 (M+H)⁺.

[0325] b)3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole

[0326] NaH (60% dispersion in mineral oil, 0.15 g, 3.8 mmole) was addedportionwise, allowing for gas evolution, to a solution of3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (0.7 g, 2.5mmole) in DMF (25 mL) at 0° C. When the NaH addition was complete,benzyl bromide (1.2 mL, 10.0 mmole) was added at 0° C. The reaction wasstirred at 0° C. for 15 minutes then at RT overnight. The reaction wasdiluted with water and extracted with ethyl acetate. The combinedextracts were dried over Na₂SO₄ and concentrated. Flash chromatographyon silica gel (33% ethyl acetate/hexanes) gave the title compound (0.9g, 93%) as an off white solid: MS (ES) m/e 385 (M+H)⁺.

[0327] c) 1-Benzyl-3-(methylaminomethyl)-1H-indole

[0328] 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole(0.9 g, 2.3 mmole) was added to a suspension of Pearlman's catalyst(about 0.30 g) in MeOH at RT in a Parr flask. The reaction was placedunder 50 p.s.i. of H₂ and shaken for 5 hr. The mixture was filteredthrough celite® and the filter pad was washed with MeOH. The filtratewas concentrated to afford the title compound (0.5 g, 86%) as a lightyellow solid: MS (ES) m/e 251 (M+H)⁺.

Preparation 18

[0329] Preparation of2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene

[0330] a) 2,3-Dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde

[0331] According to the procedure of Preparation 13 (b), exceptsubstituting 2,3-dihydro-1H-3a-azacyclopenta[a]indene (J. Med. Chem.1965, 8, 700; 0.24 g, 1.53 mmole) for the 1,3-dimethylindole, the titlecompound (0.17 g, 60%) was prepared as a yellow solid: MS (ES) m/e 186(M+H)⁺.

[0332] b) 2,3-Dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]Indene

[0333] According to the procedure of Preparation 13 (c), exceptsubstituting 2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde(0.17 g, 0.92 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde,the title compound (0.1 g, 54%) was prepared as a yellow oil: MS (ES)m/e 201 (M+H)⁺.

Preparation 19

[0334] Preparation of 1,4-dimethyl-3-(methylaminomethyl)-1H-indole

[0335] a) 1,4-Dimethyl-1H-indole

[0336] According to the procedure of Preparation 9 (a), exceptsubstituting 4-methylindole for ethyl indole-2-carboxylate, the titlecompound (1.5 g, 94%) was prepared as an amber oil: MS (ES) m/e 146.2(M+H)⁺.

[0337] b) 1,4-Dimethyl-1H-indole-3-carboxaldehyde

[0338] According to the procedure of Preparation 9 (b), exceptsubstituting 1,4-dimethyl-1H-indole for 1,3-dimethylindole, the titlecompound (1.8 g, 95%) was prepared as an amber oil: MS (ES) m/e 174.2(M+H)⁺.

[0339] c) 1,4-Dimethyl-3-(methylaminomethyl)-1H-indole

[0340] According to the procedure of Preparation 11, except substituting1,4-dimethyl-1H-indole-3-carboxaldehyde for1,3-dimethyl-1H-indole-1-carboxaldehyde, the title compound (1.9 g, 99%)was prepared as an oil: MS (ES) m/e 189.0 (M+H)⁺.

Preparation 20

[0341] Preparation of (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylicAcid Hydrochloride Salt

[0342] a) 3,3,5-Tribromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one

[0343] To a solution of 7-azaindole (5.0 g, 42.3 mmole) in H₂O (210 mL)and tert-butanol (210 mL) at RT was added Br₂ (27 mL, 529.0 mmole) over20 minutes. The reaction was stirred for 12 hr at RT and concentrated toan aqueous slurry. The reaction contents were made basic with solidNaHCO₃ and the remaining solid was filtered and washed with H₂O. Thefiltered mass was dried under high vacuum to give the title compound(14.0 g, 89%) as a brown solid: MS (ES) m/e 370 (M+H)⁺.

[0344] b) 5-Bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one

[0345] To a stirred solution of3,3,5-tribromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (2.0 g, 5.4 mmole)in acetic acid (50 mL) at RT was added Zn metal. The reaction becameexothermic and was cooled by the use of an ice bath during the initial30 minutes. After 5 hr the reaction was filtered through celite®, andthe filter pad was washed with EtOAc. The filtrate was concentratedunder vacuum and neutralized with saturated aqueous NaHCO₃ solution. Theneutralized aqueous filtrate was then extracted with EtOAc (2×200 mL),and the combined organic extracts were dried over Na₂SO₄ andconcentrated to a solid. The solid was washed with hexanes and driedunder high vacuum to give the title compound (0.36 g, 32%): MS (ES) m/e215 (M+H)⁺. This was used without further purification.

[0346] c) tert-Butyl (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylate

[0347] A solution of 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (2.0g, 9.49 mmole), tert-butyl acrylate (1.8 g, 14.1 mmole), Pd(OAc)₂ (0.32g, 1.4 mmole), tri-ortho-tolylphosphine (0.57 g, 1.9 mmole), anddiisopropylethylamine (4.9 mL, 28.2 mmole) in propionitrile (100 mL) andDMF (10 mL) was heated at reflux overnight. The dark mixture wasfiltered through celite®, and the filtrate was concentrated. Flashchromatography on silica (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) gave thetitle compound (0.80 g, 33%) as a light yellow solid. MS (ES) m/e261(M+H)⁺.

[0348] d) (E)-3-(2-Oxo-2,3-dihydro-1H-indol-5-yl)acrylic AcidHydrochloride Salt

[0349] To a stirred solution of tert-butyl(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylate (0.80 g, 3.1 mmole) inCH₂Cl₂(50 mL) at RT was added trifluoroacetic acid (20 mL). After 1 hrthe reaction solution was concentrated and the residue was dried undervacuum. An HCl solution (20 mL, 4 M in dioxane) was added and themixture was concentrated under vacuum. The remaining solid wastriturated with diethyl ether and filtered giving the title compound(0.74 g, 33%) as a white solid: MS (ES) m/e 205 (M+H−HCl)⁺.

Preparation 21

[0350] Preparation of 1-ethyl-3-(methylaminomethyl)-1H-indole

[0351] a) 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl-1-ethyl-1H-indole

[0352] According to the procedure of Preparation 17 (b), exceptsubstituting ethyl iodide (0.92 mL, 11.44 mmole) for the benzyl bromide,the title compound (0.90 g, 98%) was prepared as a white solid: MS (ES)m/e 323 (M+H)⁺.

[0353] b) 1-Ethyl-3-(methylaminomethyl)-1H-indole

[0354] According to the procedure of Preparation 17 (c), exceptsubstituting3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1-ethyl-1H-indole (0.90 g,2.80 mmole) for the3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole, thetitle compound (0.50 g, 94%) was prepared as a white solid: MS (ES) m/e189 (M+H)⁺.

Preparation 22

[0355] Preparation of 1-isopropyl-3-(methylaminomethyl)-1H-indole

[0356] a)3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-isopropyl-1H-indole

[0357] According to the procedure of Preparation 17 (b), exceptsubstituting isopropyl iodide (1.34 mL, 11.84 mmole) for the benzylbromide, the title compound (0.99 g, 99%) was prepared as a white solid:MS (ES) m/e 337 (M+H)⁺.

[0358] b) 1-ethyl-3-(methylaminomethyl)-1H-indole

[0359] According to the procedure of Preparation 17 (c), exceptsubstituting3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-isopropyl-1H-indole(0.99 g, 2.98 mmole) for the3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl)-1-benzyl-1H-indole, thetitle compound (0.49 g, 82%) was prepared as a white solid: MS (ES) m/e405 (2M+H)⁺.

Preparation 23

[0360] Preparation of 1-acetyl-3-(methylaminomethyl)-1H-indole

[0361] a) 1-Acetyl-3-(methylaminomethyl)indole

[0362] According to the procedure of Preparation 16 (a), exceptsubstituting N-acetyl-3-indole carboxaldehyde (1.33 g, 7.10 mmole), thetitle compound (1.40 g, 99%) was prepared as a light yellow oil: MS (ES)m/e 203 (M+H)⁺.

Preparation 24

[0363] Preparation of N-91H-indol-3-ylmethyl)-N-methylacrylamide

[0364] a) N-(1H-indol-3-ylmethyl)-N-methylacrylamide

[0365] Acryloyl chloride (0.33 mL, 4.10 mmole) was added to a solutionof 3-(methylaminomethyl)-1H-indole (0.60 g, 3.70 mmole) and Et₃N (1.03mL ,7.40 mmole) in CH₂Cl₂ (30 mL) at 0° C. The reaction was held at 0°C. for ten minutes, then was stirred overnight at RT. The solution wasconcentrated in vacuo and the residue was diluted with water. Thesolution was extracted with ethyl acetate, and the combined organicextracts were washed with brine and dried over Na₂SO₄. The titlecompound (0.64 g, 80%) was obtained as a light yellow solid: MS (ES) m/e215 (M+H)⁺.

Preparation 25

[0366] Preparation ofN-(1-benzyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0367] a) N-(1-Benzyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0368] According to the procedure of Preparation 24 (a), exceptsubstituting 1-benzyl-3-(methylaminomethyl)-1H-indole (1.30 g, 5.20mmole) for of 3-(methylaminomethyl)-1H-indole, the title compound (1.40g, 89%) was a brown solid: MS (ES) m/e 305 (M+H)⁺.

Preparation 26

[0369] Preparation ofN-[1-(2-dimethylamino)-1H-indol-3-ylmethyl]-N-methylacrylamide

[0370] a) N-[1-(2-dimethylamino)-1H-indol-3-ylmethyl]-N-methylacrylamide

[0371] According to the procedure of Preparation 25 (a), exceptsubstituting [1-(2-dimethylamino)]-3-(methylaminomethyl)-1H-indole (1.00g, 2.74 mmole) for of 3-(methylaminomethyl)-1H-indole, the titlecompound (0.50 g, 79%) was a yellow solid: MS (ES) m/e 463 (2M+H)⁺.

Preparation 27

[0372] Preparation of3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one

[0373] a) 8-Benzylidene-5,6,7,8-tetrahydro-quinoline

[0374] Benzaldehyde (3.59 mL, 35.30 mmole) was added to a solution of5,6,7,8-tetrahydro-quinoline (4.70 g, 35.30 mmole) in acetic anhydride(25 mL), and the solution was heated to reflux under a nitrogenatmosphere. After overnight at reflux, the reaction was concentrated invacuo. The residue was diluted with water and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated. The residue was purified by flashchromatography on silica gel (33% EtOAc/hexanes) to give the titlecompound (4.50 g, 58%) as a waxy yellow solid after drying in vacuo: MS(ES) m/e 222 (M+H)⁺.

[0375] b) 6,7-Dihydro-5H-quinolin-8-one

[0376] A solution of 8-benzylidene-5,6,7,8-tetrahydro-quinoline (4.30 g,19.4 mmole) in CH₂Cl₂ (150 mL) was reacted with ozone at −78° C. for 30minutes. Dimethyl sulfide (5 mL) was added, and the reaction was warmedto RT and stirred overnight. The mixture was concentrated in vacuo andthe residue was purified by flash chromatography on silica gel (EtOAc).The title compound (2.20 g, 79%) was obtained as an off-white solidafter drying in vacuo: MS (ES) m/e 148 (M+H)⁺.

[0377] c) 6,7-Dihydro-5H-quinolin-8-one Oxime

[0378] According to the reported procedure (J. Het. Chem. 1978, 15,249-251), 6,7-dihydro-5H-quinolin-8-one was reacted with hydroxylaminehydrochloride to afford the title compound (2.40 g, 96%) as a whitesolid after drying in vacuo: MS (ES) m/e 163 (M+H)⁺.

[0379] d) 6,7-Dihydro-5H-quinolin-8-one, O-toluenesulfonyloxime

[0380] According to the reported procedure (J. Het. Chem. 1978, 15,249-251), 6,7-dihydro-5H-quinolin-8-one oxime was reacted withp-toluenesulfonyl chloride to afford the title compound (4.00 g, 85%) asa white solid after drying in vacuo: MS (ES) m/e 317 (M+H)⁺.

[0381] e) 5,6,7,9-Tetrahydro-pyrido[2,3-b]azepin-8-one

[0382] According to the reported procedure (J. Het. Chem. 1978, 15,249-251), 6,7-dihydro-5H-quinolin-8-one, O-toluenesulfonyloxime wasreacted to afford the title compound (1.00 g, 50%) as a white solidafter drying in vacuo: MS (ES) m/e 163 (M+H)⁺.

[0383] f) 3-Bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one

[0384] A 10% solution of bromine (0.57 mL, 11.1 mmole) in CH₂Cl₂ wasadded dropwise over 1 hr to a solution of5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (1.20 g, 7.4 mmole) inCH₂Cl₂ at RT. The mixture was stirred at RT overnight, then wasconcentrated in vacuo. The residue was diluted with 10% Na₂CO₃ andextracted with EtOAc. The combined organics were dried over Na₂SO₄ andconcentrated. Flash chromatography on silica gel (EtOAc) gave the titlecompound (1.00 g, 56%) as a light yellow solid after drying in vacuo: MS(ES) m/e 241/243.

Preparation 28

[0385] Preparation of 5-bromo-2-(methylaminocarbonylmethyl)aminopyridine

[0386] a) 5-Bromo-2-(tert-butoxycarbonyl)aminopyridine

[0387] To a solution of 2-amino-5-bromopyridine (27.56 g, 159 mmole) inTHF (150 mL) was added di-tert-butyl dicarbonate (38 g, 174 mmole). Thereaction was gradually heated to reflux. Vigorous gas evolution wasobserved initially, which subsided after approximately 10 min. After 18hr at reflux, the reaction was concentrated to dryness. The residue wastriturated with 1:1 Et₂O/petroleum ether, filtered and dried undervacuum to give the title compound (34.79 g, 80%) as a white solid: ¹HNMR (400 MHz, CDCl₃) δ 8.49 (s, 1 H), 8.37 (dd, 1 H), 7.94 (d, J=9.0 Hz,1 H), 7.77 (dd, 1 H), 1.57 (s, 9 H).

[0388] b)5-Bromo-2-[N-(tert-butoxycarbonyl)-N-(methoxycarbonylmethyl)amino)pyridine

[0389] To a solution of 5-bromo-2-(tert-butoxycarbonyl)aminopyridine(25.0 g, 91.5 mmole) in DMF (400 mL) was added portionwise with stirringa 60% dispersion of NaH in mineral oil (4.0 g, 100 mmole). The reactionwas stirred for 15 min, then methyl bromoacetate (15 mL, 158.5 mmole)was added dropwise over 15 min. After stirring for 18 h at roomtemperature the reaction was concentrated to dryness. The remainingresidue was taken up in EtOAc (200 mL) and H₂O (200 mL) and filtered toremove insoluble material. The EtOAc phase was separated, washed withbrine, dried (Na₂SO₄) and concentrated to dryness. Purification by flashchromatography on silica gel (10% EtOAc/Hexane) gave the title compound(16.56 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H), 7.73 (d, J=2.5Hz, 1 H), 7.71 (d, J=2.5 Hz, 1 H), 4.69 (s, 2 H), 3.75 (s, 3 H), 1.51(s,9H).

[0390] c) 5-Bromo-2-(methoxycarbonylmethyl)aminopyridine

[0391] A 50% solution of TFA in CH₂Cl₂ (200 mL) was added to5-bromo-2-[N-(tert-butoxycarbonyl)-N-(methoxycarbonylmethyl)amino]pyridine(16.5 g, 46 mmole). After stirring for 45 min the reaction wasconcentrated to dryness, and the residue was diluted with 1.0 N Na₂CO₃(300 mL). The mixture was extracted with EtOAc (300 mL), and the organiclayer was washed with brine, dried (Na₂SO₄), and concentrated to drynessunder vacuum. The title compound (11.32 g, 100%) was obtained as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=2.3 Hz, 1 H), 7.48 (dd, 1H), 6.40 (d, J=8.8 Hz, 1 H), 4.95 (br s, 1H), 4.12 (d, J=5.5 Hz, 2 H),3.78 (s, 3H).

[0392] d) 5-Bromo-2-(methylaminocarbonylmethyl)aminopyridine

[0393] A solution of 2.0 M methylamine in MeOH (75 mL) was added to5-bromo-2-(methoxycarbonylmethyl)aminopyridine (2.9 g, 12 mmole). Thereaction was stirred for 24 h then was concentrated to dryness. Theresidue was triturated with 10% petroleum ether/Et₂O (100 mL), then wascollected and dried under vacuum to give the title compound (2.96 g,100%) as an off-white solid: MS (ES) m/e 244.2 (M+H)⁺.

Preparation 29

[0394] Preparation of Methyl 2-amino-S-bromonicotinate

[0395] a) Methyl 2-aminonicotinate

[0396] Concentrated H₂SO₄ (20 mL, 360 mmole) was added dropwise over 5minutes to a suspension of 2-aminonicotinic acid (25 g, 181 mmole) inMeOH (400 mL), and the mixture was heated at reflux; a homogeneoussolution formed within 5 min. After 72 h, the reaction was cooled toroom temperature and concentrated under vacuum. The residue was basifiedwith 1.0 N Na₂CO₃ (500 mL) (Gas evolution!) and extracted with EtOAc(500 mL). The organic layer was washed with brine, dried (Na₂SO₄), andconcentrated to dryness to give the title compound (19.6 g, 71%) as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ 8.22 (dd, 1 H), 8.13 (dd, 1 H),6.63 (dd, 1 H), 6.30 (br s, 2 H), 3.89 (s, 3 H).

[0397] b) Methyl 2-amino-5-bromonicotinate

[0398] Bromine (0.7 mL, 14 mmole) was added dropwise to a stirredsolution of methyl 2-aminonicotinate (2.0 g, 13 mmole) in HOAc (50 mL).A suspension formed within 30 min. The reaction was allowed to stir atroom temperature for 2 h, then was concentrated under vacuum. Theresidue was triturated with 1.0 N Na₂CO₃ (50 mL) and the solid wascollected by suction filtration. The solid was washed with H₂O (50 mL)and dried under vacuum to give the title compound (2.95 g, 98%) as apale yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.5 Hz, 1 H),8.23 (d, J=2.5 Hz, 1 H), 6.40 (br s, 2 H), 3.90 (s,3H).

Preparation 30

[0399] Preparation of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylic AcidHydrochloride Salt

[0400] a) tert-Butyl(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylate

[0401] A solution of 5-bromo-2-(methoxycarbonylmethyl)aminopyridine(4.69 g, 19.1 mmole, from Preparation 28 (c)), tert-butyl acrylate (11.2mL, 76.5 mmole), DIEA (6.7 mL, 38.5 mmole), Pd(OAc)₂ (215 mg, 1 mmole),and P(o-tol)₃ (583 mg, 2 mmole) in propionitrile (100 mL) was purgedwith Ar, then was heated at reflux. After 18 h, the reaction was allowedto cool to room temperature then was concentrated to dryness. Theresidue was purified by flash chromatography on silica gel (40%EtOAc/hexane) to give the title compound (5.21 g, 93%) as a white solid:¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1 H), 7.62 (dd, 1 H), 7.47 (d, J=16.0Hz, 1 H), 6.48 (d, J=8.7 Hz, 1 H), 6.17 (d, J=15.9 Hz, 1 H), 5.21 (br s,1 H), 4.20 (d, J=5.4 Hz, 2 H), 3.79 (s, 3 H), 1.52 (s, 1 H).

[0402] b) (E)-3-[6-[N-(Methoxycarbonylmethyl)amino]pyridin-3-yl]acrylicAcid Hydrochloride Salt

[0403] A solution of 50% TFA in CH₂Cl₂ (75 mL) was added to tert-butyl(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylate (5.20 g,17.8 mmole). The reaction was stirred at room temperature for 45 minthen was concentrated under vacuum. The residue was taken up in 4.0 NHCl in dioxane (75 mL), stirred for 5 min, then concentrated to drynessunder vacuum. The remaining solid was triturated with 1:1 Et₂O/petroleumether, filtered and dried under vacuum to give the title compound (4.87g, 100%) as a white solid: MS (ES) m/e 237.2 (M+H)⁺.

Preparation 31

[0404] Preparation of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic AcidHydrochloride Salt

[0405] a) tert-Butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

[0406] A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one(12.99 g, 57 mmole), tert-butyl acrylate (34 mL, 232 mmole), DIEA (21.2mL, 122 mmole), Pd(OAc)₂ (1.3 g, 5.8 mmole) and P(o-tol)₃ (3.5 g, 11.5mmole) in propionitrile (200 mL) and DMF (50 mL) was purged with Ar,then was heated at reflux. After 18 h the reaction was allowed to coolto room temperature and was concentrated to dryness. The residue waspurified by flash chromatography on silica gel (2-4% MeOH/CHCl₃). Theresulting residue was triturated with 1:1 Et₂O/petroleum ether,collected, and dried, and the resulting material was triturated with 1:1MeOH/H₂O, collected, and dried, to give the title compound (7.09 g, 45%)as an off-white solid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.70 (s, 1 H), 8.35(d, J=2.0 Hz, 1 H), 8.04 (s, 1 H), 7.50 (d, J=16.0 Hz, 1 H), 6.51 (d,J=16.0 Hz, 1 H), 2.89 (t, 2 H), 2.53 (t, 2 H), 1.48 (s, 9H); MS (ES) m/e275.2 (M+H)⁺.

[0407] b) (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicAcid Hydrochloride Salt

[0408] To tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (7.0 g,25.5 mmole) was added 1:1 TFA/CH₂Cl₂ (100 mL). The reaction was stirredfor 30 min, then was concentrated under vacuum. The residue wassuspended in 4 N HCl/dioxane (100 mL), triturated, and concentrated todryness. The resulting solid was triturated with Et₂O, collected, anddried under vacuum to give the title compound (6.55 g, 100%) as aoff-white solid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.72 (s, 1 H), 8.35 (d,J=2.0 Hz, 1 H), 8.04 (s, 1 H), 7.54 (d, J=16.0 Hz, 1 H), 6.51 (d, J=16.0Hz, 1 H), 2.91 (t, 2 H), 2.53 (t, 2 H); MS (ES) m/e 219.0 (M+H)⁺.

Preparation 32

[0409] Preparation ofN-methyl-N-(1-methyl-1H-pyrrol[2,3-b]pyridin-ylmethyl)acrylamide

[0410] A solution of acryloyl chloride (0.43 g, 5.58 mmole) in CH₂Cl₂(10 mL) was added dropwise with stirring to a solution of1-methyl-3-(methylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (0.93 g, 5.28mmole) and triethylamine (0.8 mL, 5.8 mmole) in CH₂Cl₂ (40 mL) at 0° C.under N₂. The reaction was allowed to warm to RT and stir for 1 hr, thenwas concentrated in vacuo. The residue was dissolved in 10% NaOH andextracted with CH₂Cl₂ (3×20 mL). The extracts were dried (MgSO₄),filtered, and concentrated. The residual oil was flash chromatographedon silica gel (5% MeOH/CH₂Cl₂) to give the title compound (1.0 g, 80%)as a colorless oil: MS (ES) m/e 216 (M+H)⁺.

Preparation 33

[0411] Preparation of 7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0412] a) 7-Fluoro-1H-indole-3-carboxaldehyde

[0413] According to the procedure of Preparation 11 (b), exceptsubstituting 7-fluoroindole (0.5 g, 3.7 mmole) for the 1,3dimethylindole, the title compound (0.5 g, 83%) was prepared as a waxysolid: MS (ES) m/e 164 (M+H)⁺.

[0414] b) 7-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

[0415] According to the procedure of Preparation 9 (a), exceptsubstituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) forthe ethyl indole-2-carboxylate, the title compound (0.23 g, 43%)wasprepared as a viscous oil: MS (ES) m/e 178 (M+H)⁺.

[0416] c) 7-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0417] According to the procedure of Preparation 11 (c), exceptsubstituting 7-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.23, 1.3mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the titlecompound (0.18 g, 72%) was prepared as a viscous oil: MS (ES) m/e 193(M+H)⁺.

Preparation 34

[0418] Preparation of 6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0419] a) 6-Fluoro-1H-indole-3-carboxaldehyde

[0420] According to the procedure of Preparation 11 (b), exceptsubstituting 6-fluoroindole (0.5 g, 3.7 mmole) for the1,3-dimethylindole, the title compound (0.3 g, 50%) was prepared as awaxy solid: MS (ES) m/e 164(M+H)⁺.

[0421] b) 6-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

[0422] According to the procedure of Preparation 9 (a), exceptsubstituting 6-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) forthe ethyl indole-2-carboxylate, the title compound (0.3 g, 94%) wasprepared as a viscous oil: MS (ES) m/e 178 (M+H)⁺.

[0423] c) 6-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0424] According to the procedure of Preparation 11 (c), exceptsubstituting 6-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the titlecompound (0.11 g, 35%) was prepared as a viscous oil: MS (ES) m/e 193(M+H)⁺.

Preparation 35

[0425] Preparation of 5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0426] a) 5-Fluoro-1H-indole-3-carboxaldehyde

[0427] According to the procedure of Preparation 11 (b), exceptsubstituting 5-fluoroindole (0.5 g, 3.7 mmole) for the1,3-dimethylindole, the title compound (0.3 g, 50%) was prepared as awaxy solid: MS (ES) m/e 164 (M+H)⁺.

[0428] b) 5-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

[0429] According to the procedure of Preparation 9 (a), exceptsubstituting 5-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) forthe ethyl indole-2-carboxylate, the title compound (0.16 g, 50%) wasprepared as a viscous oil: MS (ES) m/e 178 (M+H)⁺.

[0430] c) 5-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0431] According to the procedure of Preparation 11 (c), exceptsubstituting 5-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69mmole) for the 1,3 dimethyl-1H-2 -carboxaldehyde, the title compound(0.11 g, 35%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)⁺.

Preparation 36

[0432] Preparation of 4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0433] a) 4-Fluoro-1H-indole-3-carboxaldehyde

[0434] According to the procedure of Preparation 11 (b), exceptsubstituting 4-fluoroindole (0.5 g, 3.7 mmole) for the1,3-dimethylindole, the title compound (0.41 g, 68%) was prepared as awaxy solid: MS (ES) m/e 164(M+H)⁺.

[0435] b) 4-Fluoro-1-methyl-1H-indole-3-carboxaldehyde

[0436] According to the procedure of Preparation 9 (a), exceptsubstituting 4-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) forthe ethyl-indole-2-carboxylate, the title compound (0.24 g, 54%) wasprepared as a viscous oil: MS (ES) m/e 178 (M+H)⁺.

[0437] c) 4-Fluoro-1-methyl-3-(methylaminomethyl)-1H-indole

[0438] According to the procedure of Preparation 11 (c), exceptsubstituting 4-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the titlecompound (0.2 g, 77%)was prepared as a viscous oil: MS (ES) m/e 193(M+H)⁺.

Preparation 37

[0439] Preparation of (1-ethyl-5-fluoro-3-(methylaminomethyl)-1H-indole

[0440] a) 5-Fluoro-1H-indole-3-carboxaldehyde

[0441] According to the procedure of Preparation 11 (b), exceptsubstituting 5-fluoroindole (0.5 g, 3.7 mmole) for the1,3-dimethylindole, the title compound (0.3 g, 50%) was prepared as awaxy solid: MS (ES) m/e 164(M+H)⁺.

[0442] b) 1-Ethyl-5-fluoro-1H-indole-3-carboxaldehyde

[0443] According to the procedure of Preparation 9 (a), exceptsubstituting 5-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) forthe ethylindole-2-carboxylate, the title compound (0.20 g, 57%) wasprepared as a viscous oil: MS (ES) m/e 191 (M+H)⁺.

[0444] c) 1-Ethyl-5-fluoro-3-(methylaminomethyl)-1H-indole

[0445] According to the procedure of Preparation 11 (c), exceptsubstituting 1-ethyl-5-fluoro-1H-indole-3-carboxaldehyde (0.2 g,1.9mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the titlecompound (0.1 g, 50%) was prepared as a viscous oil: MS (ES) m/e 207(M+H)⁺.

Preparation 38

[0446] Preparation of4,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole

[0447] a) Ethyl 4,6-dichloro-1-methyl-1H-indole-2-carboxylate

[0448] NaH (60% dispersion in mineral oil, 0.24 g, 6 mmole) was washedwith hexanes, then was suspended in anhydrous DMF (16 mL). The mixturewas cooled to 0° C., and ethyl 4,6-dichloroindole-2-carboxylate (1.03 g,4 mmole) was added. After 2-3 min, iodomethane (1.3 mL, 20 mmole) wasadded, and the mixture was warmed to RT. The mixture became thick, andstirring became difficult for several minutes. After 0.5 hr, thereaction was cooled to 0° C. and quenched with 10% NH₄Cl (2 mL). Themixture was concentrated to dryness, and the residue was partitionedbetween Et₂O (50 mL) and H₂O (10 mL). The layers were separated and theorganic layer was washed with H₂O (5 mL), dried (MgSO₄), and filtered,and the filter pad was washed with a little CH₂Cl₂. Concentrationafforded the title compound (1.06 g, 97%) as an off-white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.34 (s, 1 H), 7.30 (s, 1 H), 7.17 (d, J=1.5 Hz, 1H), 4.39 (q, J=7.1 Hz, 2 H), 4.05 (s, 3 H), 1.42 (t, J=7.1 Hz, 3 H); MS(ES) m/e 272 and 274 (M+H)⁺.

[0449] b) N,1-Dimethyl-1H-indole-2-carboxamide

[0450] A suspension of ethyl4,6-dichloro-1-methyl-1H-indole-2-carboxylate (1.06 g, 3.90 mmole) in2.0 M CH₃NH₂/CH₃OH (40 mL) in a sealed pressure bottle was heated in anoil bath preset at 50° C. A homogeneous solution formed within 2.5 hr.The reaction was kept at 50° C. for 17.5 hr, during which time a solidprecipitated. The mixture was cooled to RT and poured into H₂O (40 mL).The resulting mixture was concentrated on the rotavap to remove themethanol, and the solid was collected by suction filtration. This waswashed with plenty of H₂O and dried in high vacuum at 45-50° C. toafford the title compound (0.99 g, 99%) as an off-white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.29 (s, 1 H), 7.16 (d, J=1.5 Hz, 1 H), 6.86 (s, 1H), 6.21 (br s, 1 H), 4.02 (s, 3 H), 3.02 (d, J=4.9 Hz, 3 H); MS (ES)m/e257 and 259 (M+H)⁺.

[0451] c) 4,6-Dichloro-1-methyl-2-(methylaminomethyl)-1H-indole

[0452] A solution of 2.0 M BH₃.DMS in THF (3.6 mL, 7.2 mmole) was addedto a solution of N,1-dimethyl-1H-indole-2-carboxamide (0.74 g, 2.88mmole) in anhydrous THF (25 mL), and the reaction was heated at reflux.After 18 hr, the reaction was cooled to 0° C. and quenched with MeOH (5mL). The solution was warmed to RT, stirred for 0.5 hr, thenconcentrated on the rotavap. The residue was re-concentrated from MeOH,then was purified by flash chromatography on silica gel (5% MeOH/CHCl₃containing 0.5% conc. NH₄OH). The title compound (197.5 mg, 28%) wasobtained as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.19 (dd, J=1.5,0.8 Hz, 1 H), 7.09 (d, J=1.5 Hz, 1 H), 6.45 (s, 1 H), 3.88 (s, 2 H),3.74 (s, 3 H), 2.50 (s, 3 H); MS (ES) m/e 212 and 214 (M+H−CH₃NH₂)⁺.

Preparation 39

[0453] Preparation of 1,7-dimethyl-3-(methylaminomethyl)-1H-indole

[0454] a) 1,7-Dimethyl-1H-indole

[0455] According to the procedure of Preparation 13 (a), exceptsubstituting 7-methylindole for the 3-methylindole, the title compound(1.95 g, 90%) was obtained as a light-colored oil: MS (ES) mmole 146.2(M+H)⁺.

[0456] b) 1,7-Dimethyl-1H-indole-3-carboxaldehyde

[0457] According to the procedure of Preparation 13 (b), exceptsubstituting 1,7-dimethylindole for the 1,2-dimethylindole, the titlecompound (1.85 g, 82%) was obtained as an off white solid: MS (ES)m/e174.2 (M+H)⁺.

[0458] c) 1,7-Dimethyl-3-(methylaminomethyl)-1H-indole

[0459] According to the procedure of Preparation 13 (c), exceptsubstituting 1,7-dimethyl-1H-indole-3-carboxylate for the1,3-dimethyl-1H-indole-2-carboxylate, the title compound (0.74 g, 98%)was obtained as an amber oil: MS (ES) mmole 189.2 (M+H)⁺.

Preparation 40

[0460] Preparation of 4-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0461] a) 4-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

[0462] According to the procedure of Preparation 13 (b), exceptsubstituting 1-methyl-4-methoxyindole for the 1,2-dimethylindole, thetitle compound (2.17 g, 93%) was obtained as an off white solid: MS (ES)m/e 190.2 (M+H)⁺.

[0463] b) 4-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0464] According to the procedure of Preparation 13 (c), exceptsubstituting 1-methyl-4-methoxy-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.0 g, 95%)was obtained as a white solid: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 41

[0465] Preparation of 5-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0466] a) 5-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

[0467] According to the procedure of Preparation 13 (a), exceptsubstituting 5-methoxy-1H-indole-3-carboxaldehyde for the3-methyl-1H-indole-3-carboxaldehyde, the title compound (0.86 g, 92%)was obtained as a light tan solid: MS (ES) m/e 190.2 (M+H)⁺.

[0468] b) 5-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0469] According to the procedure of Preparation 13 (c), exceptsubstituting 5-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.85 g,98%) was obtained as a light yellow oil: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 42

[0470] Preparation of 7-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0471] a) 7-Methoxy-1-methyl-1H-indole

[0472] According to the procedure of Preparation 13 (a), exceptsubstituting 7-methoxyindole for 3-methylindole, the title compound(1.55 g, 96%) was obtained as a tan solid: MS (ES) m/e 162.2 (M+H)⁺.

[0473] b) 7-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

[0474] According to the procedure of Preparation 13(b), exceptsubstituting 7-methoxy-1-methyl-1H-indole for the 1,2-dimethylindole,the title compound (1.6 g, 91%) was obtained as an off white solid: MS(ES) m/e 190.2 (M+H)⁺.

[0475] c) 7-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0476] According to the procedure of Preparation 13(c), exceptsubstituting 7-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.6 g, 94%)was obtained as an amber oil: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 43

[0477] Preparation of 7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0478] a) 7-Chloro-1-methyl-1H-indole

[0479] According to the procedure of Preparation 13 (a), exceptsubstituting 7-chloroindole for the 3-methylindole, the title compound(2.2 g, 100%) was obtained as a white solid: MS (ES) m/e 166.2 (M+H)⁺.

[0480] b) 7-Chloro-1-methyl-1H-indole-3-carboxaldehyde

[0481] According to the procedure of Preparation 13 (b), exceptsubstituting 7-chloro-1-methyl-1H-indole for the 1,2-dimethylindole,title compound (2.1 g, 84%) was obtained as a white solid: MS (ES) m/e194.0 (M+H)⁺.

[0482] c) 7-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0483] According to the procedure of Preparation 13 (c), exceptsubstituting 7-chloro-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.0 g, 93%)was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)⁺.

Preparation 44

[0484] Preparation of 6-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0485] a) 6-Chloro-1-methyl-1H-indole

[0486] According to the procedure of Preparation 13 (a), exceptsubstituting 6-chloroindole for the 3-methylindole, the title compound(2.2 g, 100%) was obtained as a white solid: MS (ES) m/e 166.2.0 (M+H)⁺.

[0487] b) 6-Chloro-1-methyl-1H-indole-3-carboxaldehyde

[0488] According to the procedure of Preparation 13 (b), exceptsubstituting 6-chloro-1-methyl-1H-indole for the 1,2-dimethylindole,title compound (2.2 g, 88%) was obtained as an amber oil: MS (ES) m/e194.2 (M+H)⁺.

[0489] c) 6-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0490] According to the procedure of Preparation 13 (c), exceptsubstituting 6-chloro-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%)was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)⁺.

Preparation 45

[0491] Preparation of 5-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0492] a) 5-Chloro-1-methyl-1H-indole

[0493] According to the procedure of Preparation 13 (a), exceptsubstituting 5-chloroindole for the 3-methylindole, the title compound(2.0 g, 91%) was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)⁺.

[0494] b) 5-Chloro-1-methyl-1H-indole-3-carboxaldehyde

[0495] According to the procedure of Preparation 13 (b), exceptsubstituting 5-chloro-1-methyl-1H-indole for the 1,2-dimethylindole,title compound (2.0 g, 83%) was obtained as an white solid: MS (ES) m/e194.0′(M+H)⁺.

[0496] c) 5-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0497] According to the procedure of Preparation 13 (c), exceptsubstituting 5-chloro-1-methyl-1H-indole-3-carboxaldehyde for the,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%)was obtained as an amber oil: MS (ES) m/e 209.0 (M+H)⁺.

Preparation 46

[0498] Preparation of 4-chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0499] a) 4-Chloro-1-methyl-1H-indole

[0500] According to the procedure of Preparation 13 (a), exceptsubstituting 4-chloroindole for the 3-methylindole, the title compound(2.2 g, 100%) was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)⁺.

[0501] b) 4-Chloro-1-methyl-1H-indole-3-carboxaldehyde

[0502] According to the procedure of Preparation 13 (b), exceptsubstituting 4-chloro-1-methyl-1H-indole for the 1,2-dimethylindole,title compound (1.9 g, 76%) was obtained as an off-white solid: MS (ES)m/e 194.0 (M+H)⁺.

[0503] c) 4-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole

[0504] According to the procedure of Preparation 13 (c), exceptsubstituting 4-chloro-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.75 g,78%) was obtained as a yellow solid: MS (ES) m/e 209.0 (M+H)⁺.

Preparation 47

[0505] Preparation of 1,1-dimethyl-3-(methylaminomethyl)-3H-indene

[0506] a) 1,1-Dimethyl-3H-indene-3-carboxaldehyde

[0507] The title compound was obtained in quantitative yield accordingto established literature procedures (Chem. Pharm. Bull. 1986, 34,390-395; Tet. Lett. 1993, 34, 2979): ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s,1 H), 8.05 (d, 2 H), 7.35 (m, 4 H), 1.40 (s, 6 H).

[0508] b) 1,1-Dimethyl-3-(methylaminomethyl)-3H-indene

[0509] According to the procedure of Preparation 12, except substituting1,1-dimethyl-3H-indene-3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (3 g, 81%) wasobtained as a reddish oil: MS (ES) m/e 188.2 (M+H)⁺.

Preparation 48

[0510] Preparation of 7-hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0511] a) 7-Benzyloxy-1-methyl-1H-indole

[0512] According to the procedure of Preparation 13 (a), exceptsubstituting 7-benzyloxyindole for the 3-methylindole, the titlecompound (4.8 g, 100%) was obtained as an amber oil: MS (ES) m/e 238.0(M+H)⁺.

[0513] b) 7-Benzyloxy-1-methyl-1H-indole-3-carboxaldehyde

[0514] According to the procedure of Preparation 13 (b), exceptsubstituting 7-benzyloxy-1-methyl-1H-indole for the 1,2-dimethylindole,title compound (4.5 g, 85%) was obtained as an oil: MS (ES) m/e 266.0(M+H)⁺.

[0515] c) 7-Benzyloxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0516] According to the procedure of Preparation 13 (c), exceptsubstituting 7-benzyloxy-1-methyl-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (3.7 g, 88%)was obtained as an oil: MS (ES) m/e 281.2 (M+H)⁺.

[0517] d) 7-Hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0518] According to the literature procedure (J. Org. Chem. 1978, 43,4195-96), 7-benzyloxy-1-methyl-3-(methylaminomethyl)-1H-indole washydrogenated to afford the title compound (300 mg, 79%) as a brownsolid: MS (ES) m/e 191.2 (M+H)⁺.

Preparation 49

[0519] Preparation of 3-(methylaminomethyl)-1,2,7-trimethyl-1H-indole

[0520] a) 1,2,7-Trimethyl-1H-indole

[0521] According to the procedure of Preparation 13 (a), exceptsubstituting 2,7-dimethylindole for the 3-methylindole, the titlecompound (960 mg, 87%) was obtained as an oil: MS (ES) m/e 160.2 (M+H)⁺.

[0522] b) 1,2,7-Trimethylindole-3-carboxaldehyde

[0523] According to the procedure of Preparation 13 (b), exceptsubstituting 1,2,7-trimethyl-1H-indole for the 1,4-dimethylindole, thetitle compound (800 mg, 62%) was obtained as a light tan solid: MS (ES)m/e 188.2 (M+H)⁺.

[0524] c) 3-(Methylaminomethyl)-1,2,7-trimethyl-1H-indole

[0525] According to the procedure of Preparation 13 (

[0526] c) except substituting 1,2,7-trimethyl-1H-indole-3-carboxaldehydefor the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (570mg, 71%) was obtained as an oil which slowly crystallized: MS (ES) m/e405.4 (2M+H)⁺.

Preparation 50

[0527] Preparation of 7-chloro-3-(methylaminomethyl)-1H-indole

[0528] a) 7-Chloro-1H-indole-3-carboxaldehyde

[0529] According to the procedure of Preparation 13 (b), exceptsubstituting 7-chloroindole for the 1,2-dimethylindole, the titlecompound (0.48 g, 44%) was obtained as a white solid afterrecrystallization from hot EtOAc: MS (ES) m/e 180.0 (M+H)⁺.

[0530] b) 7-Chloro-3-(methylaminomethyl)-1H-indole

[0531] According to the procedure of Preparation 13 (c), exceptsubstituting 7-chloro-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (440 mg,92%) was obtained as an off white solid: MS (ES) m/e 195.2 (M+H)⁺.

Preparation 51

[0532] Preparation of 2-(methylaminomethyl)naphthalene

[0533] To a stirred solution of 40 wt % methylamine in H₂O (50 mL, 581mmole) in THF (50 mL) at 0° C. was added 2-(bromomethyl)naphthalene (10g, 43 mmole) in one portion. The reaction was allowed to warm to RT andstirred for 16 hr, then was then concentrated under vacuum. The residuewas taken up in Et₂O and washed with 1.0 N NaOH then with brine, dried(Na₂SO₄), and concentrated to dryness. Purification by flashchromatography on silica gel (98:2 to 9:1 CHCl₃/methanol containing 5%NH₄OH) gave the title compound (3.95 g, 54%) as a clear oil: ¹H NMR (400MHz, CDCl₃) δ 7.85 (m, 3 H), 7.79 (s, 1 H), 7.49 (m, 3 H), 3.94 (s, 2H), 2.53 (s, 3 H).

Preparation 52

[0534] Preparation of 3-(methylaminomethyl)quinoline

[0535] A solution of 3-quinolinecarboxaldehyde (1.5 g,10 mmole), 2.0 MCH₃NH₂/MeOH (10 mL, 20 mmole), glacial AcOH (0.6 mL, 10 mmole), andNaBH₃CN (0.35 g, 11 mmole) in MeOH (20 mL) was stirred at RT overnight,then was concentrated in vacuo. The residue was diluted with 5% NaOH andextracted with CH₂Cl₂. The combined organic extracts were washed withbrine, dried over MgSO₄, and concentrated. Flash chromatography onsilica gel (10% MeOH/CH₂Cl₂) gave the title compound (0.83 g, 24%) as aslightly yellow viscous oil: MS (ES) m/e 173 (M+H)⁺.

Preparation 53

[0536] Preparation of(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1.8-naphthyridin-3-yl)acrylicAcid Hydrochloride Salt

[0537] a) tert-Butyl(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

[0538] According to the procedure of Preparation 31 (a), exceptsubstituting tert-butyl methacrylate (4.7 g, 33.2 mmole) for thetert-butyl acrylate, the title compound (2.7 g, 42 %) was prepared as ayellow solid: MS (ES) m/e 289 (M+H)⁺.

[0539] b)(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicAcid Hydrochloride Salt

[0540] According to the procedure of Preparation 31 (b), exceptsubstituting tert-butyl(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate(2.7 g, 9.3 mmole) for the tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate, thetitle compound (2.5 g, 99%) was prepared as a white solid: MS (ES) m/e232 (M+H)⁺.

Preparation 54

[0541] Preparation of(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicAcid Hydrochloride Salt

[0542] a) tert-Butyl(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

[0543] According to the procedure of Preparation 31 (a), exceptsubstituting tert-butyl crotonate (4.7 g, 33.2 mmole) for the tert-butylacrylate, the title compound (3.7 g, 58%) was prepared as a yellowsolid: MS (ES) m/e 289 (M+H)⁺.

[0544] b)(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicAcid Hydrochloride Salt

[0545] According to the procedure of Preparation 31 (b), exceptsubstituting tert-butyl(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate(3.7 g, 12.8 mmole) for the tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate, thetitle compound (3.4 g, 99%) was prepared as a white solid: MS (ES) m/e232 (M+H)⁺.

Preparation 55

[0546] Preparation of7-bromo-4-methyl-1,2,4,5-tetrahydropyrido[2,3-e]-1,4-diazepin-3-one

[0547] a)5-Bromo-3-[N-(tert-butoxycarbonyl)-N-methylaminomethyl]-2-[N-(tert-butoxycarbonyl)amino]pyridine

[0548] To a solution of 2-amino-5-bromo-3-(methylaminomethyl)pyridine(3.8 g, 17.6 mmole), from Preparation 5 (a), in THF was addeddi-tert-butyl dicarbonate (8.8 g, 40.5 mmole). The reaction was heatedto reflux for 12 hr then was concentrated under vacuum. Flashchromatography on silica gel (1:1 hexanes/EtOAc) gave the title compound(6.2 g, 85%) as a white waxy solid: MS (ES) m/e 416 (M+H)⁺.

[0549] b)5-Bromo-2-[(ethoxycarbonyl)methylamino]-3-(methylaminomethyl)-2-[N-(tert-butoxycarbonyl)amino]PyridineBis-trifluoroacetic Acid Salt

[0550] To a suspension of 60% NaH (0.46 g, 11.5 mmole) in THF (100 mL)at RT was added5-bromo-3-[N-(tert-butoxycarbonyl)-N-methylaminomethyl]-2-[N-(tert-butoxycarbonyl)amino]pyridine(4.0 g, 9.61 mmole). After 30 min, ethyl bromoacetate (1.8 g, 10.6mmole) was added. The reaction was stirred at RT for 12 hr, then wasquenched with H₂O (5 mL) and concentrated. The residue was dissolved inEtOAc (200 mL), and the solution was washed with H₂O (100 mL), driedover Na₂SO₄, and concentrated under high vacuum to a light yellow solid.This was dissolved in CH₂Cl₂ (50 mL) and trifluoroacetic acid (20 mL).After 2 hr, the reaction was concentrated under vacuum and the residuewas purified flash chromatography on silica gel (95:5 CHCl₃/CH₃OH). Thetitle compound (4.1 g, 80%) was obtained as a yellow solid: MS (ES)m/e302 (M+H)⁺.

[0551] c)7-Bromo4-methyl-1,2,4,5-tetrahydropyrido[2,3-e]-1,4-diazepin-3-one

[0552] To a solution of5-bromo-2-[(ethoxycarbonyl)methylamino]-3-(methylaminomethyl)-2-[N-(tert-butoxycarbonyl)amino]pyridinebis-trifluoroacetic acid salt (4.1 g, 7.7 mmole) in toluene was addedtriethylamine (3.3 mL, 23.7 mmole). The reaction was heated at refluxfor 72 hr then concentrated under vacuum. Flash chromatography on silicagel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH) gave the title compound (1.4g, 72%) as a tan solid: MS (ES) m/e 256 (M+H)⁺.

Preparation 56

[0553] Preparation of(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-acrylicAcid Hydrochloride Salt

[0554] a) tert-butyl(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylate

[0555] A solution of3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (1.00 g, 4.15mmole), tert-butyl acrylate (0.67 mL, 4.60 mmole), DIEA (1.45 mL, 8.30mmole), Pd(OAc)₂ (0.09 g, 0.42 mmole) and P(o-tol)₃ (0.25 g, 0.85 mmole)in propionitrile (25 mL) was purged with N₂ and then heated at refluxovernight. The dark mixture was filtered through a pad of celite®, andthe filter pad was rinsed with acetonitrile (250 mL). The filtrate wasconcentrated in vacuo, and the residue was purified by flashchromatography on silica gel (ethyl acetate). The title compound (0.70g, 58%) was obtained as a light yellow solid after drying in vacuo: MS(ES) m/e 289 (M+H)⁺.

[0556] b)(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-acrylicAcid Hydrochloride Salt

[0557] According to the procedure of Preparation 31 (b), exceptsubstituting tert-butyl(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylate(0.70 g, 2.40 mmole) for the tert-butyl(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate, thetitle compound (0.49 g, 77%) was obtained as an off-white solid afterdrying in vacuo: MS (ES) m/e 233 (M+H)⁺.

Preparation 57

[0558] Preparation of 1-(2-hydroxyethyl)-3-(methylaminomethyl)-1H-indole

[0559] According to the reported literature procedure (J. Org. Chem.1998, 63, 6721-6726) except substituting3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (3.70 g, 12.60mmole) for the 5-bromoindole, the title compound (4.00 g, 93%) wasobtained as a yellow solid after drying in vacuo: MS (ES) m/e 338(M+H)⁺.

Preparation 58

[0560] Preparation of 2-chloro-1-methyl-2-(methylaminomethyl)-1H-indole

[0561] a) 2-Chloro-1H-indole-3-carboxaldehyde

[0562] To DMF (30 mL) with stirring at 0° C. was added dropwisephosphorus oxychloride (10 mL, 107 mmole) over 5 minutes. The reactionwas stirred for an additional 15 minutes, then oxindole (6.0 g, 45mmole) was added portionwise over 5 min. The reaction was allowed towarm to RT and stirred for 18 h then was carefully poured into ice water(350 mL). The solution was stirred for 6 h after which time a suspensionformed. The solids were filtered off, washed with cold water, presseddry and dried under vacuum to give the title compound (6.83 g, 84%) as ayellowish solid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.0 (s, 1 H), 8.05 (dd, 1H), 7.43 (dd, 1 H), 7.23-7.31 (m, 2 H); MS (ES) m/e 179.0 (M+H)⁺.

[0563] b) 2-Chloro-1-methyl-1H-indole-3-carboxaldehyde

[0564] NaH (60% dispersion in mineral oil) (0.9 g, 22.5 mmole) was addedportionwise over 5 min to a solution of2-chloro-1H-indole-3-carboxaldehyde (3.8 g, 21.2 mmole) and iodomethane(1.5 mL, 24 mmole) in DMF (50 mL) with stirring at 0° C. The reactionwas allowed to warm to RT and stir for 4 h, then was concentrated undervacuum. The remaining residue was taken up in EtOAc, and the solutionwas washed with water then brine, dried (MgSO₄), and concentrated todryness. Trituration with 1:1 Et₂O/petroleum ether, filtration, anddrying under vacuum gave the title compound (3.10 g, 76%) as anoff-white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1 H), 8.29 (m, 1H), 7.33 (m, 3 H), 3.81 (s, 3 H); MS (ES) m/e 194.0 (M+H)⁺.

[0565] c) 2-Chloro-1-methyl-2-(methylaminomethyl)-1H-indole

[0566] According to the procedure of Preparation 12, except substituting2-chloro-1-methyl-1H-indole-3-carboxaldehyde (3.0 g, 15.5 mmole) for the1-methylindole-3-carboxaldehyde, the title compound (2.91 g, 90%) wasprepared as an oil: ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=7.9 Hz, 1 H),7.22 (m, 2 H), 7.13 (m, 1 H), 3.92 (s, 2 H), 3.71 (s, 3 H), 2.44 (s, 3H).

Preparation 59

[0567] Preparation of3-(benzhydrylideneamino)-6-bromo-3,4-dihydro-1H-1.8-naphthyridin-2-one

[0568] NaH (60% dispersion in mineral oil, 1.2 g, 30 mmole) was addedportionwise over 10 min to a solution of N-(diphenylmethylene)glycineethyl ester (8.0 g, 30 mmole) in DMF (150 mL) with stirring under Ar at0° C. The reaction was stirred for 15 min, then2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (5.0 g, 14.4 mmole)was added in one portion. The reaction was allowed to warm to RT andstir for 18 h, then was concentrated under vacuum. The remaining residuewas taken up in EtOAc (150 mL), hexane (150 mL), and H₂O (150 mL). Theresulting suspension was triturated and filtered, and the solid wasdried under vacuum to give the title compound (3.27 g, 56%) as anoff-white solid: ¹H NMR (400 MHz, d₆-DMSO) δ 10.92 (s, 1 H), 8.23 (s, 1H), 7.86 (s, 1 H), 7.26-7.55 (m, 10 H), 4.05 (dd, 1 H), 3.10 (t, 2 H);MS (ES) m/e 406.0 (M+H)⁺.

Preparation 60

[0569] Preparation of 2-(methylaminomethyl)benzofuran

[0570] To a stirred solution of 2-benzofurancarboxaldehyde (2.22 g, 15.2mmole) in MeOH (5 mL) was added 2 M methylamine in MeOH (15 mL), HOAc(0.86 mL, 15 mmole), and NaBH₃CN (1.0 g, 15.9 mmole). The reaction wasstirred for 18 h at RT then concentrated under vacuum. The remainingresidue was taken up in Et₂O, and the solution was washed with 1 N NaOHthen brine, dried (Na₂SO₄), and concentrated to dryness. Purification byflash chromatography on silica gel (5% (5% NH₄OH in MeOH)/CHCl₃) gavethe title compound (1.23 g, 50%) as a pale yellow oil: MS (ES) m/e 162.4(M+H)⁺.

Preparation 61

[0571] Preparation of methyl1-methyl-3-(methylaminomethyl)-1H-indole-7-carboxylate

[0572] a) Methyl 1-methyl-1H-indole-7-carboxylate

[0573] According to the procedure of Preparation 9 (a), exceptsubstituting methyl indole-7-carboxylate for the ethylindole-2-carboxylate, the title compound (2.4 g, 90%) was obtained as anoil: MS (ES) m/e 190.2 (M+H)⁺.

[0574] b) N-Methyl-7-methoxycarbonyl-1H-indole-3-carboxaldehyde

[0575] According to the procedure of Preparation 13 (b), exceptsubstituting methyl 1-methyl-1H-indole-7-carboxylate for the1,3-dimethylindole, the title compound (1.8 g, 70%) was obtained as awhite solid: MS (ES) m/e 218.2 (M+H)⁺.

[0576] c) Methyl 1-methyl-3-(methylaminomethyl)-1H-indole-7-carboxylate

[0577] According to the procedure of Preparation 12, except substituting1-methyl-7-methoxycarbonyl-1H-indole 3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (1.7 g, 92%) wasobtained as an oil: MS (ES) m/e 233.2 (M+H)⁺.

Preparation 62

[0578] Preparation of methyl1-methyl-3-(methylaminomethyl)-1H-indole-6-carboxylate

[0579] a) Methyl 1-methyl-1H-indole-6-carboxylate

[0580] According to the procedure of Preparation 9 (a), exceptsubstituting methyl indole-6-carboxylate for the ethylindole-2-carboxylate, the title compound (2.5 g, 95%) was obtained aswhite solid: MS (ES) m/e 190.2 (M+H)⁺.

[0581] b) N-Methyl-7-methoxycarbonyl-1H-indole-3-carboxaldehyde

[0582] According to the procedure of Preparation 13 (b), exceptsubstituting methyl 1-methyl-1H-indole-6-carboxylate for the1,3-dimethylindole, the title compound (2.6 g, 98%) was obtained as awhite solid: MS (ES) m/e 218.2 (M+H)⁺.

[0583] c) Methyl 1-methyl-3-(methylaminomethyl)-1H-indole-6-carboxylate

[0584] According to the procedure of Preparation 12, except substituting1-methyl-7-methoxycarbonyl-1H-indole 3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (1.9 g, 63%) wasobtained as an oil: MS (ES) m/e 233.2 (M+H)⁺.

Preparation 63

[0585] Preparation of 6-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0586] a) 6-Methoxy-1-methyl-1H-indole

[0587] According to the procedure of Preparation 9 (a), exceptsubstituting 6-methoxy-1H-indole for the ethyl indole-2-carboxylate, thetitle compound (2.3 g, 95%) was obtained as an oil: MS (ES) m/e 162.2(M+H)⁺.

[0588] b) 6-Methoxy-1-methyl-1H-indole-3-carboxaldehyde

[0589] According to the procedure of Preparation 13 (b), exceptsubstituting 6-methoxy-1-methyl-1H-indole for the 1,3-dimethylindole,the title compound (2.3 g, 82%) was obtained as a tan solid: MS (ES) m/e190.2 (M+H)⁺.

[0590] c) 6-Methoxy-1-methyl-3-(methylaminomethyl)-1H-indole

[0591] According to the procedure of Preparation 12, except substituting6-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the2-methylindole-3-carboxaldehyde, the title compound (2.1 g, 87%) wasobtained as an oil: MS (ES) m/e 205.2 (M+H)⁺.

Preparation 64

[0592] Preparation of 7-fluoro-3-(methylaminomethyl)-1H-indole

[0593] a) 7-Fluoro-1H-indole-3-carboxaldehyde

[0594] According to the procedure of Preparation 13 (b), exceptsubstituting 7-fluoroindole (0.5 g, 3.7 mmole) for the1,3-dimethylindole, the title compound (0.3 g, 55%) was prepared as awaxy solid: MS (ES) m/e 164 (M+H)⁺.

[0595] b) 7-Fluoro-3-(methylaminomethyl)-1H-indole

[0596] According to the procedure of Preparation 13 (c),exceptsubstituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) forthe 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.5 g,90%) was prepared as a viscous oil: MS (ES) m/e 179 (M+H)⁺.

[0597] Preparation of 4-fluoro-3-(methylaminomethyl)-1H-indole

[0598] a) 4-Fluoro-1H-indole-3-carboxaldehyde

[0599] According to the procedure of Preparation 13 (b), exceptsubstituting 4-fluoroindole (0.4 g, 2.45 mmole) for the1,3-dimethylindole, the title compound (0.31 g, 72%) was prepared as aviscous oil: MS (ES) m/e 164 (M+H)⁺.

[0600] b) 4-Fluoro-3-(methylaminomethyl)-1H-indole

[0601] According to the procedure of Preparation 13 (c),exceptsubstituting 4-fluoro-1H-indole-3-carboxaldehyde for the1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound was preparedas a viscous oil: MS (ES) m/e 179 (M+H)⁺.

Preparation 66

[0602] Preparation of6-bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

[0603] a) 2-Amino-5-bromo-3-[(2-methoxyethyl)aminomethyl]pyridine

[0604] 2-Methoxyethylamine (1.49 mL, 17.16 mmole) was added to asolution of 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (1.49g, 4.29 mmole) and DIEA (2.24 mL, 12.87 mmole) in CH₂Cl₂ (10 mL) at RT.The reaction was stirred overnight then was concentrated in vacuo. Theresidue was diluted with water and the solution was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated to afford the title compound (1.00 g, 90%)as a light brown liquid after drying in vacuo: MS (ES) m/e 260/262(M+H)⁺.

[0605] b)6-Bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

[0606] 1,1′-Carbonyldiimidazole (0.74 g, 4.60 mmole) was added to asolution of 2-amino-5-bromo-3-[(2-methoxyethyl)aminomethyl]pyridine(1.00 g, 3.80 mmole) in 1,2-dichloroethane (35 mL) at RT. The reactionwas heated at 65° C. with stirring overnight, then was concentrated invacuo. Flash chromatography on silica gel (5% MeOH/(CHCl₃) gave titlecompound (0.90 g, 83%) as a yellow solid after drying in vacuo: MS (ES)m/e 286/288 (M+H)⁺.

[0607] The following examples illustrate methods for preparing thebiologically active compounds of this invention from intermediatecompounds such as those described in the foregoing Preparations.

Example 1

[0608] Preparation of(E)-3-(2-aminopyrimidin-5-yl)-N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0609] a) N-Methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

[0610] To a solution of 2-methyl-3-(methylaminomethyl)indole (1.5 g, 8.6mmole) and triethylamine (1.7 g, 17.3 mmole) in CH₂Cl₂ at 5° C. under anitrogen atmosphere was added acryloyl chloride (0.86 g, 9.48 mmole).After 1 hr the reaction solution was poured into H₂O (100 mL) and thelayers were separated. The organic fraction was washed with H₂O (100 mL)followed by brine and then dried over Na₂SO₄. Concentration under vacuumgave the title compound as an orange oil which solidified under highvacuum: MS (ES) m/e 457 (2M+H)⁺. This material was used without furtherpurification.

[0611] b)(E)-3-(2-Aminopyrimidin-5-yl)-N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0612] A solution of N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide(1.18 g, 6.5 mmole), 2-amino-5-bromopyrimidine (0.5 g, 2.9 mmole),Pd(OAc)₂ (0.11 g, 0.49 mmole), tri-ortho-tolylphosphine (0.17 g, 0.55mmole), and diisopropylethylamine (1.5 mL, 8.6 mmole) in propionitrile(100 mL) and DMF (10 mL) was heated at reflux overnight. The darkmixture was filtered through celite®, and the filtrate was concentrated.Flash chromatography on silica gel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH)gave the title compound (1.2 g, 65%): MS (ES) m/e 372 (M+H)⁺.

Example 2

[0613] Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide

[0614] According to the procedure of Example 1 (b), except substituting6-bromo-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one (1.2 g, 5.0mmole) for the 2-amino-5-bromopyrimidine, the title compound (73%) wasprepared as a light yellow solid: MS (ES) m/e 390 (M+H)⁺.

Example 3

[0615] Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide

[0616] a) N-Methyl-N-(1-methyl-indol-3-ylmethyl)acrylamide

[0617] According to the procedure of Example 1 (a), except substituting1-methyl-3-(methylaminomethyl)indole for the2-methyl-3-(methylaminomethyl)indole, the title compound (1.7 g, 99%)was prepared as an orange oil that solidified under vacuum: MS (ES) m/e229 (M+H)⁺. This material was used without further purification.

[0618] b)(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide

[0619] According to the procedure of Preparation 1 (b), exceptsubstituting N-methyl-N-(1-methyl-indol-3-ylmethyl)acrylamide (1.7 g,7.5 mmole) for N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide, thetitle compound (70%) was prepared as a light yellow solid: MS (ES) m/e390 (M+H)⁺.

Example 4

[0620] Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide

[0621] To a solution of (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylicacid hydrochloride salt (0.50 g, 2.1 mmole), hydroxybenzotriazolemonohydrate (0.31 g, 2.3 mmole), diisopropylethylamine (0.80 mL, 4.6mmole), and 2-methyl-3-(methylaminomethyl)indole (0.40 g, 2.3 mmole) inDMF (50 mL) at RT was added EDC (0.46, 2.3 mmole). After 12 hr thereaction solution was concentrated under vacuum and the residue waspurified by flash chromatography on silica gel (9:1 CHCl₃/CH₃OHcontaining 5% NH₄OH) to give the title compound (0.66 g, 88%) as a lightyellow solid: MS (ES) m/e 361 (M+H)⁺.

Example 5

[0622] Preparation of(E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide

[0623] According to the procedure of Example 4, except substituting(E)-3-(3H-imidazo[4,5-b]pyridin-6-yl) acrylate (0.14 g, 0.74 mmole),from Preparation 6, for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,and substituting 1-methyl-3-(methylaminomethyl)indole (0.14 g, 0.81mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the titlecompound (0.23 g, 89%) was prepared as a light yellow solid: MS (ES) m/e346 (M+H)⁺.

Example 6

[0624] Preparation of(E)-3-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide

[0625] According to the procedure of Example 4, except substituting(E)-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (0.11g, 0.53 mmole), from Preparation 7, for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,and substituting 1-methyl-3-(methylaminomethyl) indole (0.10 g, 0.59mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the titlecompound (0.16 g, 82%) was prepared as a light yellow solid: MS (ES)m/e363 (M+H)⁺.

Example 7

[0626] Preparation of(E)-3-[6-amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

[0627] a) Ethyl (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

[0628] A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (5.0g, 21.9 mmole), from Preparation 4, ethyl acrylate (3.3 g, 32.9 mmole),Pd(OAc)₂ (1.1 g, 0.74 mmole), tri-ortho-tolylphosphine (1.3 g, 4.4mmole), and diisopropylethylamine (11.4 mL, 65.7 mmole) in propionitrile(200 mL) and DMF (25 mL) was heated at reflux overnight. The darkmixture was filtered through celite®, and the filtrate was concentrated.Flash chromatography on silica gel (9:1 CHCl₃/CH₃OH containing 5% NH₄OH)gave the title compound (3.0 g, 59%) as a light yellow solid: MS (ES)m/e 233 (M+H)⁺.

[0629] b) (E)-3-[6-Amino-5-(2-carboxyethyl)pyridin-3-yl]acrylic acidhydrochloride salt

[0630] Ethyl (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (1.54 g, 6.6 mmole) was dissolved in acetic acid (25 mL) andconcentrated hydrochloric acid (25 mL) and the solution was heated to100° C. After 6 hr the solution was concentrated and the residue wasdried under high vacuum. The resulting solid was triturated with diethylether and filtered to give a 1.46 g of a mixture of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) acrylic acidhydrochloride salt (82%) and the title compound (18%), both as whitesolids: MS (ES) m/e 218 (M+H)+(major) and MS (ES) m/e 236 (M+H)⁺(minor). This mixture was used without further purification.

[0631] c)(E)-3-[6-Amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

[0632] According to the procedure of Example 4, except substituting amixture (1.46 g) of(E)-3-[6-amino-5-(2-carboxyethyl)pyridin-3-yl]acrylic acid hydrochloridesalt and (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) acrylicacid hydrochloride salt for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,the title compound (0.47 g) was prepared as a light yellow solid: MS(ES) m/e 549 (M+H)⁺.(E)-N-Methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide(1.56 g) was also obtained as a light yellow solid: MS (ES) m/e 375(M+H)⁺.

Example 8

[0633] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0634] EDC (0.56 g, 2.93 mmole) was added to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (0.48 g, 2.93 mmole),1-ethyl-3-(methylaminomethyl)-1H-indole (0.50 g. 2.66 mmole), HOBt H₂O(0.40 g, 2.93 mmole) and diisopropylethylamine (0.93 mL, 5.32 mmole) inDMF (30 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (10%MeOH/CHCl₃) gave title compound (0.46 g, 52%) as a yellow solid afterdrying in vacuo: MS (ES) m/e 335 (M+H)⁺.

Example 9

[0635] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1-isopropyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0636] EDC (0.51 g, 2.64 mmole) was added to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (0.43 g, 2.64 mmole),1-isopropyl-3-(methylaminomethyl)indole (0.49 g, 2.40 mmole), HOBt.H₂O(0.36 g, 2.64 mmole) and diisopropylethylamine (0.84 mL 4.80 mmole) inDMF (40 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (10%MeOH/CHCl₃) gave the title compound (0.49 g, 58%) as a yellow solidafter drying in vacuo: MS (ES) m/e 349 (M+H)⁺.

Example 10

[0637] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-91H-indol-3-ylmethyl)-N-methylacrylamide

[0638] EDC (1.03 g, 5.40 mmole) was added to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (0.89 g, 5.40 mmole),1-acetyl-3-(methylaminomethyl)indole (1.00 g, 4.95 mmole), HOBt.H₂O(0.73 g.,5.40 mmole) and diisopropylethylamine (1.72 mL, 9.90 mmole) inDMF (50 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (5%MeOH/CHCl₃) gave the title compound (0.90 g, 52%) as a light yellowsolid after drying in vacuo: MS (ES) m/e 307 (M+H)⁺.

Example 11

[0639] Preparation of(E)-N-(1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0640] A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.64g, 2.80 mmole), N-(1H-indol-3-ylmethyl)-N-methylacrylamide (0.60 g, 2.80mmole), Pd(OAc)₂ (0.06 g, 0.28 mmole), tri-ortho-tolylphosphine (0.17 g,0.56 mmole) and diisopropylethylamine (0.73 mL, 4.2 mmole) inpropionitrile (50 mL) was deoxygenated, then was heated to reflux underN₂ overnight. The dark mixture was filtered through a pad of celite®,and the filter pad was rinsed with acetonitrile (250 mL). The filtratewas concentrated in vacuo, and the residue was purified by flashchromatography on silica gel (10% MeOH/CHCl₃). The title compound (0.37g, 37%) was obtained as a light yellow solid after drying in vacuo: MS(ES) m/e 361 (M+H)⁺.

Example 12

[0641] Preparation of(E)-N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0642] A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.05g, 4.60 mmole), N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-acrylamide(1.40 g, 4.60 mmole), Pd(OAc)₂ (0.10 g, 0.46 mmole),tri-ortho-tolylphosphine (0.28 g, 0.92 mmole) and diisopropylethylamine(1.20 mL 6.90 mmole) in propionitrile (75 mL) was deoxygenated, then wasand heated to reflux under a N₂ overnight. The dark mixture was filteredthrough a pad of celite®, and the filter pad was rinsed withacetonitrile (300 mL). The filtrate was concentrated in vacuo, and theresidue was purified by flash chromatography on silica gel (5%MeOH/CHCl₃). The title compound (0.70 g. 35%) was obtained as a lightyellow solid after drying in vacuo: MS (ES) m/e 451 (M+H)⁺.

Example 13

[0643] Preparation of(E)-N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0644] A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.61g, 2.70 mmole),N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-acrylamide(1.00 g, 3.50 mmole), Pd(OAc)₂ (0.08 g, 0.35 mmole),tri-ortho-tolylphosphine (0.21 g, 0.70 mmole), and diisopropylethylamine(0.91 mL, 5.25 mmole) in propionitrile (70 mL) was deoxygenated, thenwas and heated to reflux under a N₂ overnight. The dark mixture wasfiltered through a pad of celite®, and the filter pad was rinsed withacetonitrile (250 mL). The filtrate was concentrated in vacuo, and theresidue was purified by flash chromatography on silica gel (10%MeOH/CHCl₃ containing 5% NH₄OH in the MeOH). The title compound (0.20 g.13%) was obtained as a light yellow solid after drying in vacuo: MS (ES)m/e432 (M+H)⁺.

Example 14

[0645] Preparation of(E)-N-methyl-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide

[0646] A solution of3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (0.60 g, 2.50mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (0.85 g,3.75 mmole), Pd(OAc)₂ (0.06 g, 0.25 mmole), tri-ortho-tolylphosphine(0.15 g, 0.50 mmole) and diisopropylethylamine (0.87 mL, 5.00 mmole) inpropionitrile (50 mL) was deoxygenated, then was and heated to refluxunder a N₂ overnight. The dark mixture was filtered through a pad ofcelite®, and the filter pad was rinsed with acetonitrile (200 mL). Thefiltrate was concentrated in vacuo, and the residue was purified byflash chromatography on silica gel (10% MeOH/CHCl₃). The title compound(0.35 g. 35%) was obtained as a light tan solid after drying in vacuo:MS (ES) m/e 246 (M+H)⁺.

Example 15

[0647] Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-[6-(pyridin-2-ylamino)pyridin-3-yl]acrylamide

[0648] a) N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0649] To a stirred solution of 1-methyl-3-(methylaminomethyl)-1H-indole(1.0 g, 5.7 mmole) and Et₃N (0.8 mL, 5.7 mmole) in CH₂Cl₂ (50 mL) at 0°C. was added acryloyl chloride (0.47 mL, 5.8 mmole) in one portion.After stirring for 1 h the reaction was washed with cold H₂O and brine,then was dried (MgSO₄) and concentrated under vacuum. This material wasused without further purification.

[0650] b)(E)-N-Methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-[6-(pyridin-2-ylamino)pyridin-3-yl]acrylamide

[0651] To a solution ofN-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide, from Example 1 (a),in propionitrile (50 mL) was added 5-bromo-2,2′-dipyridylamine (1.2 g,4.8 mmole), DIEA (1.8 mL, 10.3 mmole), Pd(OAc)₂ (112 mg, 0.5 mmole), andP(o-tol)₃ (304 mg, 1 mmole). The reaction was purged with Ar thenstirred at reflux for 16 h. After cooling to room temperature thereaction was concentrated to dryness under vacuum. Flash chromatographyon silica gel (3% (5% NH₄OH/MeOH)/CHCl₃), trituration with 1:1Et₂O/petroleum ether, filtration, and drying under vacuum gave the titlecompound (1.24 g, 65%) as an off-white solid: MS (ES) m/e 398.2 (M+H)⁺.

Example 16

[0652] Preparation of(E)-N-methyl-N-(2-methylbenzo[b]thiophen-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0653] a) N-(Benzo[b]thiophen-3-ylmethyl)-N-methylacrylamide

[0654] According to the procedure of Example 15 (a), except substituting2-methyl-3-(methylaminomethyl)benzo[b]thiophene (1.0 g, 5.2 mmole) for1-methyl-3-(methylaminomethyl)-1H-indole, the title compound wasprepared. This was used without further purification.

[0655] b)(E)-N-Methyl-N-(2-methylbenzo[b]thiophen-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0656] According to the procedure of Example 15 (b), except substituting6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.3 g, 5.7 mmole) for the5-bromo-2,2′-dipyridylamine, the title compound (0.849 g, 42%) wasprepared as a white solid: MS (ES) m/e 392.2 (M+H)⁺.

Example 17

[0657] Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

[0658] a) N-(1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

[0659] According to the procedure of Example 15 (a), except substituting1-methyl-2-(methylaminomethyl)-1H-indole (1.2 g, 6.9 mmole) for the1-methyl-3-(methylaminomethyl)-1H-indole, the title compound wasprepared. This was used without further purification.

[0660] b)(E)-N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

[0661] According to the procedure of Example 15 (b), except substituting5-bromo-2-(methylaminocarbonylmethyl)aminopyridine (1.5 g, 6.2 mmole)for the 5-bromo-2,2′-dipyridylamine, the title compound (1.7 g, 72%) wasprepared as a white solid: MS (ES) m/e 392.2 (M+H)⁺.

Example 18

[0662] Preparation of(E)-3-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0663] a) N-(1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

[0664] According to the procedure of Example 15 (a), except substituting1-methyl-2-(methylaminomethyl)-1H-indole (1.2 g, 6.9 mmole) for the1-methyl-3-(methylaminomethyl)-1H-indole, the title compound wasprepared. This was used without further purification.

[0665] b)(E)-3-(6-Amino-5-(methoxycarbonyl)pyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0666] According to the procedure of Example 15 (b), except substitutingmethyl 2-amino-5-bromonicotinate (1.4 g, 6.1 mmole) for the5-bromo-2,2′-dipyridylamine, the title compound (1.78 g, 77%) wasprepared as a white solid: MS (ES) m/e379.2 (M+H)⁺.

Example 19

[0667] Preparation of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

[0668] To a stirred solution of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylic acidhydrochloride salt (2.0 g, 7.3 mmole) in 1:1 DMF/CH₂Cl₂ (100 mL) wasadded 2-methyl-3-(methylaminomethyl)indole (1.3 g, 7.5 mmole), Et₃N (2.1mL, 15 mmole), and HOBt H₂O (1.0 g, 7.4 mmole), followed by EDC (1.4 g,7.3 mmole). After stirring at room temperature for 18 h the reaction wasconcentrated to dryness. The residue was taken up in EtOAc, and thesolution was washed with H₂O then brine, dried (Na₂SO₄), andconcentrated under vacuum. The remaining residue was purified by flashchromatography on silica gel (4% MeOH/CHCl₃) to give the title compound(2.08 g, 73%) as an off-white solid: MS (ES) m/e 393.2 (M+H)⁺.

Example 20

[0669] Preparation of(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide

[0670] To a stirred solution of(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide(0.5 g, 1.3 mmole) in dioxane (30 mL) was added 1 N NaOH (2 mL, 2mmole). After stirring for 18 h the reaction was neutralized with 1 NHCl (2 mL, 2 mmole) and concentrated to near dryness. The resultingsuspension was diluted with H₂O and filtered. The solid was washed withH₂O and dried under vacuum to give the title compound (505 mg, 100%) asa off-white solid: MS (ES) m/e 379.2 (M+H)⁺.

Example 21

[0671] Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

[0672] To(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide(0.7 g, 1.8 mmole) was added a solution of 2.0 M methylamine in MeOH (50mL). After stirring for 72 h the reaction was concentrated to dryness.The residue was triturated with Et₂O, filtered, and dried under vacuumto give the title compound (0.703 g, 100%) as an off-white solid: MS(ES) m/e 392.2 (M+H)⁺.

Example 22

[0673] Preparation of(E)-3-(2-aminopyrimidin-5-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide

[0674] A solution of 2-amino-5-bromopyrimidine (0.27 g, 1.55 mmole),N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide (0.5g, 2.33 mmole), Pd(OAc)₂ (0.037 g, 0.163 mmole), P(o-tolyl)₃ (0.085 g,0.28 mmole), and (i-Pr)₂NEt (0.42 mL, 2.33 mmole) in propionitrile (20mL) was degassed then heated to reflux. After 18 hr the mixture wascooled to RT and concentrated. Flash chromatography on silica gel (10%MeOH/CH₂Cl₂) gave the title compound (0.100 g, 18%): MS (ES) m/e 363(M+H)⁺.

Example 23

[0675] Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0676] According to the procedure of Example 22, except substituting6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.352 g, 1.55 mmole) forthe 2-amino-5-bromopyrimidine, the title compound (0.14 g, 16%) wasprepared as a white powder: MS (ES) m/e 376 (M+H)⁺.

Example 24

[0677] Preparation of(E)-N-(2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0678] EDC (0.192 g, 1.0 mmole) was added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (0.254 g, 1.0 mmole),2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene (0.2 g,1.0 mmole), HOBt.H₂O (0.135 g, 1.0 mmole), and Et₃N (0.15 mL, 1.1 mmole)in DMF (20 mL) at RT. The reaction was stirred overnight, then waspoured into H₂O (50 mL) and extracted with CH₂Cl₂ (2×30 mL). Thecombined extracts were washed with brine and dried (MgSO₄). Flashchromatography on silica gel (5% MeOH/CH₂Cl₂) gave the title compound(0.1 g, 25%) a yellow solid: MS (ES) m/e 401 (M+H)⁺.

Example 25

[0679] Preparation of(E)-N-(1-ethyl-5-fluoro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0680] According to the procedure of Example 24, except substituting(1-ethyl-5-fluoro-3-(methylaminomethyl)-1H-indole (0.1 g, 0.49 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.028 g, 15%) was prepared as a white powder: MS(ES) m/e 407 (M+H)⁺.

Example 26

[0681] Preparation of(E)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0682] According to the procedure of Example 24, except substituting5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.13 g, 0.67 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.1 g, 37%) was prepared as a slightly yellowcrystalline solid: MS (ES) m/e 393 (M+H)⁺.

Example 27

[0683] Preparation of(E)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0684] According to the procedure of Example 24, except substituting6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.12 g, 0.59 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.1 g, 43%) was prepared as a white crystallinesolid: MS (ES) m/e 393 (M+H)⁺.

Example 28

[0685] Preparation of(E)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0686] According to the procedure of Example 24, except substituting7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.18 g, 0.93 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,the title compound (0.1 g, 27%) was prepared as a white powder: MS (ES)m/e 393 (M+H)⁺.

Example 29

[0687] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0688] According to the procedure of Example 24, except substituting6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.11 g, 0.59 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.098 g, 0.59mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.1 g, 27%) was prepared as awhite powder: MS (ES) m/e 339 (M+H)⁺.

Example 30

[0689] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4,6-dichloro-1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

[0690] EDC (84.4 mg, 0.44 mmole) was added all at once to a solution of(E)-3-(6-aminopyridin-3-yl)acrylic acid (65.7 mg, 0.40 mmole),4,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole (107.0 mg, 0.44mmole), HOBt.H₂O (59.5 mg, 0.44 mmole), and Et₃N (0.14 mL, 1.0 mmole) inanhydrous DMF (4 mL) at RT. After 17 hr, the reaction was concentratedto dryness and the residue was re-concentrated from CHCl₃/xylenes (2×).Flash chromatography on silica gel (7% MeOH in 1:1 EtOAc/CHCl₃) gave theR_(f) 0.44 component (10% MeOH in 1:1 EtOAc/CHCl₃) as a foam. This wassolidified by re-concentration from MeOH/EtOAc/CHCl₃ several times. Thismaterial was triturated with hot EtOAc/MeOH, and the mixture was cooledto 0° C. The title compound was collected by suction filtration. Thefiltrate was concentrated and the residue was triturated with EtOAc toafford additional title compound. The combined desired solids were driedin high vacuum at 50-60° C. to afford the title compound (108.9 mg, 70%)as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) 1.8:1 mixture of amiderotamers; δ 8.08 -8.20 (2×s, 1 H), 7.70 -7.90 (2×d, 1 H), 7.57-7.70(2×s, 1 H), 7.46 (d, J=15.2 Hz, 1 H), 7.18 (s, 1 H), 6.97 (d, J=15.2 Hz,1 H), 6.45 and 6.15 (2×m, 4 H), 5.02 and 4.82 (2×s, 2 H),3.60-3.80(2×s,3 H), 2.99 and 3.11(2×s, 3 H); MS (ES) me 239 and 391(M+H)⁺.

Example 31

[0691] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1,4-dimethyl-1H-indole-3-ylmethyl)-N-methylacrylamide

[0692] To a stirred solution of1,4-dimethyl-3-(methylaminomethyl)-1H-indole (188.2 mg, 1 mmole) and(E)-3-(6-aminopyridin-3-yl)acrylic acid (164 mg, 1 mmole) in dry DMF (12mL) containing dry Et₃N (4 mL) was added HOBt.H₂O (153 mg, 1 mmole) andEDC (191.8 mg, 1 mmole). The reaction was stirred overnight under argonat ambient temperature, then was concentrated in vacuo. The residue waspartitioned between EtOAc and 5% NaHCO₃ solution, and the layers wereseparated. The organic layer was washed with brine, dried (MgSO₄),filtered, and concentrated. Flash chromatography on silica gel affordedthe title compound (120 mg, 36%) as a white solid: MS (ES) m/e 335.2(M+H)⁺. Anal. Calcd for C₂OH₂₂N₄O.0.25 H₂O: C, 70.88; H, 6.69; N, 16.53.Found: C, 71.11; H, 6.72; N, 16.36.

Example 32

[0693] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0694] According to the procedure of Example 31, except substituting4-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-indole, the title compound (100 mg,29%) was obtained as a light yellow solid: MS (ES) m/e 351.2 (M+H)⁺.Anal. Calcd for C₂OH₂₂N₄0₂ 0.25 H₂O: C, 67.68; H, 6.39; N, 15.79. Found:C, 67.31; H, 6.2 1; N, 15.97.

Example 33

[0695] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0696] According to the procedure of Example 3 1, except substituting5-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (110mg, 31%) was obtained as a light tan solid: MS (ES) m/e 351.2 (M+H)⁺.Anal. Calcd for C₂OH₂₂N₄O₂.0.75 H₂O: C, 66.01; H, 6.51; N, 15.39. Found:C, 65.83; H, 6.29; N, 15.60.

Example 34

[0697] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

[0698] According to the procedure of Example 31, except substituting7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for thedimethyl-3-(methylaminomethyl)-1H-indole, the title compound (180 mg,52%) as obtained as a yellow solid: MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.25 H₂O: C, 63.51; H, 5.47; N, 15.59. Found: C,63.55; H, 5.32; N, 15.68.

Example 35

[0699] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0700] According to the procedure of Example 31, except substituting7-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (140mg, 40%) was obtained as a tan solid: MS (ES) m/e 351.2 (M+H)⁺. Anal.Calcd for C₂₀H₂₂N₄O₂.0.5 H₂O: C, 66.83; H, 6.45; N, 15.58. Found: C,66.81; H, 6.41; N, 15.19.

Example 36

[0701] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(6-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

[0702] According to the procedure of Example 31, except substituting6-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (176mg, 50%) was obtained as a yellow solid: MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.5 H₂O: C, 62.72; H, 5.54; N, 15.40. Found: C,62.79; H, 5.20; N, 15.85.

Example 37

[0703] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(5-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

[0704] According to the procedure of Example 31, except substituting5-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole the title compound wasobtained as a tan solid (176 mg, 54%): MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.25 H₂O: C, 63.51; H, 5.47; N, 15.59. Found: C,63.63; H, 5.84; N, 15.83.

Example 38

[0705] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

[0706] According to the procedure of Example 31, except substituting4-Chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-indole the title compound wasobtained as a tan solid (150 mg, 42%): MS (ES) m/e 355.2 (M+H)⁺. Anal.Calcd for C₁₉H₁₉ClN₄O.0.25 H₂O: C, 63.51; H, 5.47; N, 15.59. Found: C,63.33; H, 5.38; N, 15.34.

Example 39

[0707] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(3.3-dimethyl-3H-indene-1-ylmethyl)-N-methylacrylamide

[0708] According to the procedure of Example 31, except substituting1,1-dimethyl-3-(methylaminomethyl)-3H-indene for the1,4-dimethyl-3-(methylaminomethyl-1H-indole, the title compound (43 mg,13%) was obtained as a white solid: MS (ES) m/e 334.2 (M+H)⁺. Anal.Calcd for C₂₁H₂₃N₃O.0.75 H₂O: C, 72.70; H, 7.12; N, 12.11. Found: C,72.38; H, 6.80; N, 11.69.

Example 40

[0709] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0710] According to the procedure of Example 31, except substituting7-hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound wasobtained as a tan solid (60 mg, 17.9%): MS (ES) m/e 337.2 (M+H)⁺. Anal.Calcd for C₁₉H₂₀N₄O₂.1.0 H₂O: C, 64.39; H, 6.26; N, 15.81. Found: C,63.99; H, 5.78; N, 15.54.

Example 41

[0711] Preparation of(E)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)-acrylamide

[0712] a) N-Methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide

[0713] To a cold solution (ice bath) of3-(methylaminomethyl)-1,2,7-trimethyl-1H-indole (570 mg, 2.8 mmole) indry CH₂Cl₂ (24 mL) was added dry Et₃N (0.25 mL, 2.9 mmole). The reactionwas stirred in the cold under argon for 2 h then was poured into H₂O (40mL). The layers were separated, and the organic layer was washed withbrine, dried (MgSO₄), filtered, and concentrated. The title compound(0.7 g, 97%) was obtained as a light orange solid: MS (ES) m/e 257.2(M+H)⁺.

[0714] b)(E)-N-Methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)-acrylamide

[0715] A mixture ofN-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide (256 mg, 1mmole) and 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (227 mg, 1mmole) in propionitrile (20 mL) was treated with DIEA (0.3 mL), Pd(OAc)₂(29 mg, 0.13 mmole), and tri-o-tolylphosphine (50 mg, 0.16 mmole). Thereaction was heated at reflux under argon for 10 h, then was cooled toRT and filtered through supercel. The filtrate was concentrated and theresidue was purified by flash chromatography on silica gel to afford thetitle compound (100 mg, 25%) as an off-white solid: MS (ES) m/e 403.2(M+H)⁺. Anal. Calcd for C₂₄H₂₆N₄O₂.2.75 H₂O: C, 63.77; H, 7.02; N,12.39. Found: C, 63.81; H, 7.25; N, 11.90.

Example 42

[0716] Preparation of(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylamide

[0717] A solution of 7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole(104.3 mg, 0.5 mmole) and(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid(109.1 mg, 0.5 mmole) in dry DMF (8 mL) was treated with dry Et₃N (0.2mL), HOBt.H₂O (76.5 mg, 0.5 mmole) and EDC (96 mg, 0.5 mmole). Thesolution was stirred at RT under argon for 20 h, then was concentrated.The oily residue was dissolved in MeOH and the solution was cooled. Theprecipitated solid was collected, washed with cold MeOH, and dried togive the title compound (95 mg, 47%): MS (ES) m/e 409.2 (M+H)⁺. Anal.Calcd for C₂₂H₂₁ClN₄O₂.0.25 H₂O: C, 63.92; H, 5.24; N, 13.55. Found: C,63.56; H, 5.14; N, 13.73.

Example 43

[0718] Preparation of(E)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylamide

[0719] According to the procedure of Example 42, except substituting7-chloro-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(25 mg, 13%) was obtained as an off white solid after chromatography onsilica gel: MS (ES) m/e 395.0 (M+H )⁺

Example 44

[0720] Preparation of(E)-2,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0721] According to the procedure of Example 4, except substituting(E)-2-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicacid hydrochloride salt (0.50 g, 1.8 mmole) for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,the title compound (0.64 g, 89%) was prepared as a light yellow solid:MS (ES) m/e 389 (M+H)⁺.

Example 45

[0722] Preparation of(E)-3,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0723] According to the procedure of Example 4, except substituting(E)-3-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylicacid hydrochloride salt (0.50 g, 1.8 mmole) for the(E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,the title compound (0.67 g, 92%) was prepared as a light yellow solid:MS (ES) m/e 389 (M+H)⁺.

Example 46

[0724] Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e]-1.4-diazepin-7-yl)acrylamide

[0725] According to the procedure of Example 1, except substituting7-bromo-4-methyl-1,2,4,5-tetrahydropyrido[2,3-e]-1,4-diazepin-3-one(0.50 g, 1.9 mmole) for the 2-amino-5-bromopyrimidine, the titlecompound (0.30 g, 62%) was prepared as a light yellow solid: MS (ES) m/e404 (M+H)⁺.

Example 47

[0726] Preparation of (E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide

[0727] EDC (0.18 g, 0.96 mmole) was added to a solution of(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylic acidhydrochloride salt (0.24 g, 0.87 mmole),2-methyl-3-(methylaminomethyl)indole (0.15 g, 0.87 mmole), HOBt H₂O(0.13 g., 0.96 mmole) and diisopropylethylamine (0.45 mL, 2.61 mmole) inDMF (15 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Preparative HPLC on a Waters C-18 ODSA column(gradient: 20-100% H₂O/CH₃CN) gave the title compound (0.13 g, 38%) as alight yellow solid after drying in vacuo: MS (ES) m/e 389 (M+H)⁺.

Example 48

[0728] Preparation of(E)-N-[1-(2-hydroxyethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0729] EDC (0.54 g, 2.80 mmole) was added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (0.71 g, 2.80 mmole),1-(2-hydroxyethyl)-3-(methylaminomethyl)-1H-indole (0.52 g, 2.55 mmole),HOBt H₂O (0.38 g., 2.80 mmole) and diisopropylethylamine (1.11 mL, 6.40mmole) in DMF (25 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (20%EtOH/EtOAc) gave title compound (0.28 g, 27%) as an off-white solidafter drying in vacuo: MS (ES) m/e 405 (M+H)⁺.

Example 49

[0730] Preparation of(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide)

[0731] EDC (0.06 g, 0.30 mmole) was added to a solution of(E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylic acidhydrochloride salt (0.07 g, 0.27 mmole),1-methyl-3-(methylaminomethyl)-1H-indole (0.05 g, 0.27 mmole), HOBt.H₂O(0.04 g., 0.30 mmole) and diisopropylethylamine (0.14 mL, 0.81 mmole) inDMF (15 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (20%EtOH/EtOAc) gave title compound (0.05 g, 48%) as an off-white solidafter drying in vacuo: MS (ES) m/e 389 (M+H)⁺.

Example 50

[0732] Preparation of(E)-N-[1-(2-hydroxyethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0733] EDC (0.35 g, 1.81 mmole) was added to a solution of(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (0.42 g, 1.65 mmole),1-ethyl-3-(methylaminomethyl)-1H-indole (0.31 g, 1.65 mmole), HOBt.H₂O(0.24 g., 1.81 mmole) and diisopropylethylamine (0.86 mL, 4.95 mmole) inDMF (15 mL) at RT. The reaction was stirred overnight then wasconcentrated in vacuo. The residue was diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄. Flash chromatography on silica gel (10%EtOH/EtOAc) gave title compound (0.39 g, 61%) as a light yellow solidafter drying in vacuo: MS (ES) m/e 389 (M+H)⁺.

Example 51

[0734] Preparation of(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide

[0735] According to the procedure of Example 19, except substituting7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole (1.4 g, 6.7 mmole) forthe 2-methyl-3-(methylaminomethyl)indole, the title compound (2.38 g,84%) was prepared as a pale yellow solid: MS (ES) m/e 427.0 (M+H)⁺.

Example 52

[0736] Preparation of(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0737] According to the procedure of Example 20, except substituting(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide(0.75 g, 1.8 mmole) for the(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide,the title compound (0.746 g, 100%) was prepared as a white solid: MS(ES) m/e 413.2 (M+H)⁺.

Example 53

[0738] Preparation of(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide

[0739] According to the procedure of Example 21, except substituting(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide(0.75 g, 1.8 mmole) for the(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide,the title compound (0.721 g, 94%) was prepared as a white solid: MS (ES)m/e 426.0 (M+H)⁺.

Example 54

[0740] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0741] According to the procedure of Example 31, except substituting2-chloro-1-methyl-2-(methylaminomethyl)-1H-indole (0.7 g, 3.0 mmole) forthe 1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound(0.935 g, 88%) was obtained as an off-white solid: MS (ES) m/e 355.2(M+H)⁺.

Example 55

[0742] Preparation of(E)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0743] According to the procedure of Example 24, except substituting2-chloro-1-methyl-2-(methylaminomethyl)-1H-indole (0.7 g, 3.0 mmole) forthe 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, thetitle compound (1.03 g, 84%) was obtained as a white solid: MS (ES) m/e409.0 (M+H)⁺.

Example 56

[0744] Preparation of(E)-N-(naphthalen-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0745] According to the procedure of Example 24, except substituting2-(methylaminomethyl)naphthalene (0.55 g, 3.2 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, thetitle compound (0.871 g, 73%) was obtained as a white solid: MS (ES) m/e372.2 (M+H)⁺.

Example 57

[0746] Preparation of(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-amino-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0747] a)(E)-N-(1-Methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(benzhydrylideneamino)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide

[0748] According to the procedure of Example 15, except substituting3-(benzhydrylideneamino)-6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one(3.5 g, 8.6 mmole) for the 5-bromo-2,2′-dipyridylamine, the titlecompound (3.72 g, 78%) was obtained as a pale yellow solid: MS (ES) m/e554.4 (M+H)⁺.

[0749] b)(E)-N-(1-Methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-amino-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0750] To a suspension of(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(benzhydrylideneamino)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide(0.5 g, 0.9 mmole) in dioxane (15 mL) was added 1 N HCl (10 mL) withstirring at RT. After approximately 5 min the suspension cleared up thengradually reformed. After stirring for 1 h the reaction was neutralizedwith 1 N NaOH (10 mL) and concentrated to near dryness under vacuum. Theresulting suspension was diluted with H₂O (20 mL) and filtered, and thesolid was rinsed with cold H₂O and dried under vacuum. The slightlypinkish solid was triturated with Et₂O, filtered, and dried under vacuumto give the title compound (248 mg, 71%) as an off-white solid: MS (ES)m/e 390.4 (M+H)⁺.

Example 58

[0751] Preparation of(E)-N-(benzofuran-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0752] According to the procedure of Example 4, except substituting(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt (1.60 g, 6.3 mmole) for the(E)-3-(2-oxo[2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt,and substituting 2-(methylaminomethyl)benzofuran (1.20 g, 6.9 mmole) forthe 2-methyl-3-(methylaminomethyl)indole, the title compound (2.0 g,90%) was prepared as a tan solid: MS (ES) m/e 363 (M+H)⁺.

Example 59

[0753] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0754] According to the procedure of Example 31, except substitutingmethyl 1-methyl-3-(methylaminomethyl)-1H-indole-7-carboxylate for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (150mg, 34%) was obtained, after trituration with diethyl ether, as anoff-white solid: MS (ES) m/e379.2 (M+H)⁺. Anal. Calcd forC₂₁H₂₂N₄O₃.0.25 H₂O: C, 65.87; H, 5.92; N, 14.63. Found: C, 66.02; H,5.71; N, 14.29.

Example 60

[0755] Preparation of(E)-3-(aminopyridin-3-yl)-N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide

[0756] According to the procedure of Example 31, except substituting3-(methylaminomethyl)-1,2,7-trimethyl-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (120mg, 29%) was obtained, after trituration with ethyl acetate, as a lightyellow solid: MS (ES) m/e 349.0 (M+H)⁺. Anal. Calcd for C₂₁H₂₄N₄O.H₂O:C, 68.82; H, 7.69; N, 15.29. Found: C, 68.42; H, 6.86; N, 15.61.

Example 61

[0757] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide

[0758] According to the procedure of Example 31, except substituting7-chloro-3-(methylaminomethyl)-1H-indole for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (150mg, 25%) was obtained, after trituration with ethyl acetate, as a lightyellow solid: MS (ES) m/e 341.0 (M+H)⁺. Anal. Calcd for C₁₈H₁₇N₄O.0.25H₂O: C, 62.60; H, 5.10; N, 16.22. Found: C, 62.29; H, 5.01; N, 16.32.

Example 62

[0759] Preparation of(E)-N-(5-chloro-1-methyl-1H-indol-3ylmethyl-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0760] According to the procedure of Example 42, except substituting5-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 49%) was obtained as a light tan solid: MS (ES) m/e 409.0(M+H)⁺. Anal. Calcd for C₂₂H₂₁ClN₄O₂.0.5 H₂O: C, 63.23; H, 5.32; N,13.40. Found: C, 63.19; H, 5.23; N, 13.45.

Example 63

[0761] Preparation of (E)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0762] According to the procedure of Example 42, except substituting6-chloro-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(125 mg, 61%) was obtained as a light tan solid: MS (ES) m/e 409.0(M+H)⁺. Anal. Calcd for C₂₂H₂₁ClN₄O₂.0.25 H₂O: C, 63.92; H, 5.24; N,13.55. Found: C, 63.96; H, 4.98; N, 13.66.

Example 64

[0763] Preparation of (E)-N-(1,7-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0764] According to the procedure of Example 42, except substituting1,7-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 51%) was obtained as a white solid: MS (ES) m/e 389.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.25 H₂O: C, 70.29; H, 6.28; N, 14.25. Found:C, 70.06; H, 6.23; N, 14.29

Example 65

[0765] Preparation of(E)-N-(1,6-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0766] According to the procedure of Example 42, except substituting1,6-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(95 mg, 49%) was obtained as a white solid: MS (ES) m/e389.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.75 H₂O: C, 68.72; H, 6.39; N, 13.93. Found:C, 68.98; H, 6.07; N, 13.81.

Example 66

[0767] Preparation of(E)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0768] According to the procedure of Example 42, except substituting1,4-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(90 mg, 46%) was obtained as a white solid: MS (ES) m/e 389.0 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.5 H₂O: C, 69.50; H, 6.33; N, 14.10. Found:C, 69.40; H, 6.24; N, 14.20.

Example 67

[0769] Preparation of(E)-N-(1,5-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0770] According to the procedure of Example 42, except substituting1,5-dimethyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 51%) was obtained as a white solid: MS (ES) m/e 389.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₂.0.125 H₂O: C, 70.70; H, 6.25; N, 14.34.Found: C, 70.75; H, 6.15; N, 14.38.

Example 68

[0771] Preparation of(E)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0772] According to the procedure of Example 42, except substituting7-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(85 mg, 42%) was obtained as an off-white solid: MS (ES) m/e 405.2(M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃: C, 68.30; H, 5.95; N, 13.85. Found:C, 67.95; H, 5.94; N, 13.94.

Example 69

[0773] Preparation of(E)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0774] According to the procedure of Example 42, except substituting7-hydroxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(200 mg, 51%) was obtained as a tan solid: MS (ES) m/e 391.2 (M+H)⁺.Anal. Calcd for C₂₂H₂₂N₄O₃.0.75 H₂O: C, 65.41; H, 5.85; N, 13.86. Found:C, 65.25; H, 5.95; N, 13.79.

Example 70

[0775] Preparation of (E)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0776] According to the procedure of Example 42, except substituting4-chloro-1-methyl-3-(methylaminomethyl for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(100 mg, 49%) was obtained as a white solid: MS (ES) m/e 409.0 (M+H)⁺.Anal. Calcd for C₂₂H₂₁ClN₄O₂.0.75 H₂O: C, 62.55; H, 5.36; N, 13.26.Found: C, 62.71; H, 5.24; N, 13.15.

Example 71

[0777] Preparation of(E)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1.8-naphthyridin-3-yl)acrylamide

[0778] According to the procedure of Example 42, except substituting4-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(65 mg, 32%) was obtained as an off-white solid: MS (ES) m/e 405.2(M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃.1.25 H₂O: C, 64.69; H, 6.19; N,13.33. Found: C, 64.49; H, 5.94; N, 13.76

Example 72

[0779] Preparation of(E)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0780] According to the procedure of Example 42, except substituting5-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(90 mg, 44%) was obtained as an off-white solid: MS (ES) m/e 405.2(M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃ 0.5 H₂O: C, 66.81; H, 6.09; N, 13.55.Found: C, 66.67; H, 5.96; N, 13.87.

Example 73

[0781] Preparation of (E)3-(6-aminopyridin-3-yl)-N-(7-carboxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0782] A solution of(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide(76 mg, 0.2 mmole) in methanol (4 mL), water (2 mL), and tetrahydrofuran(2 mL) was treated with LiOH (39 mg, 1.6 mmole), and the reaction wasstirred at ambient temperature for 48 h. The mixture was filtered, andthe filtrate was acidified to pH 4.0-4.5 with 1.0 N HCl. The precipitatewas collected, washed with water and dried giving the title compound (25mg, 35%) as a white solid: MS (ES) m/e 365.2 (M+H)⁺. Anal. Calcd forC₂₀H₂₀N₄O₃.0.25 H₂O: C, 65.11: H, 5.60; N, 15.18. Found: C, 64.83; H,5.52; N, 15.07.

Example 74

[0783] Preparation of(E)-N-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0784] According to the procedure of Example 42, except substituting6-methoxy-1-methyl-3-(methylaminomethyl)-1H-indole for the7-chloro-I-methyl-3-(methylaminomethyl)-1H-indole, the title compound(65 mg, 32%) was obtained as a yellow solid: MS (ES) m/e405.2 (M+H)⁺.Anal. Calcd for C₂₃H₂₄N₄O₃.H₂O: C, 65.38; H, 6.20; N, 13.26. Found: C,65.36; H, 5.98; N, 13.16.

Example 75

[0785] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(6-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0786] According to the procedure of Example 31, except substitutingmethyl 1-methyl-3-(methylaminomethyl)-1H-indole-6-carboxylate for the1,4-dimethyl-3-(methylaminomethyl)-1H-indole, the title compound (168mg, 39%) was obtained, after silica gel chromatography, as a whitesolid: MS (ES) m/e 379.2 (M+H)⁺. Anal. Calcd for C₂₁H₂₂N₄O₃ 0.125 H₂O:C, 66.25; H, 5.93; N, 14.71. Found: C, 66.60; H, 6.13; N, 14.18.

Example 76

[0787] Preparation of(E)-N-(3.3-dimethyl-3H-indene-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0788] According to the procedure of Example 42, except substituting3,3-dimethyl-1-(methylaminomethyl)-3H-indene for the7-chloro-1-methyl-3-(methylaminomethyl)-1H-indole, the title compound(48 mg, 12%) was obtained, after silica gel chromatography, as a tansolid: MS (ES) m/e 388.2 (M+H)⁺. Anal. Calcd for C₂₃H₂₄N₄O₃.0.375 H₂O:C, 73.31; H, 6.51; N, 10.66. Found: C, 72.91; H, 6.37; N, 11.16.

Example 77

[0789] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0790] According to the procedure of Example 24, except substituting4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.11 g, 37%) was prepared as anoff-white powder: MS (ES) m/e 339 (M+H)⁺.

Example 78

[0791] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0792] According to the procedure of Example 24, except substituting5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.14 g, 41%) was prepared as anoff-white powder: MS (ES) m/e 339 (M+H)⁺.

Example 79

[0793] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide

[0794] According to the procedure of Example 24, except substituting7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene,and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.1 g, 27%) was prepared as anoff-white powder: MS (ES) m/e 339 (M+H)⁺.

Example 80

[0795] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide

[0796] According to the procedure of Example 24, except substituting4-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, andsubstituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.285 g, 1.74mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.2 g, 36%) was prepared as awhite powder: MS (ES) m/e 325 (M+H)⁺.

Example 81

[0797] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide

[0798] According to the procedure of Example 24, except substituting7-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, andsubstituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.285 g, 1.74mmole) for the(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acidhydrochloride salt, the title compound (0.1 g, 18%) was prepared as awhite powder: MS (ES) m/e 325 (M+H)⁺.

Example 82

[0799] Preparation of(E)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0800] According to the procedure of Example 24, except substituting4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.13 g, 0.68 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene),the title compound (0.15 g, 56%) was prepared as an off-white powder: MS(ES) m/e 393 (M+H)⁺.

Example 83

[0801] Preparation of(E)-N-(quinolin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0802] According to the procedure of Example 24, except substituting3-(methylaminomethyl)quinoline (0.12 g, 0.67 mmole) for the2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene), thetitle compound (0.1 g, 40%) was prepared as an off-white powder: MS (ES)m/e 373 (M+H)⁺.

Example 84

[0803] Preparation of(E)-N-(naphthalen-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0804] According to the procedure of Example 24, except substitutingN-methyl-1-naphthalenemethylamine hydrochloride (0.162 g, 0.95 mmole)for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene),the title compound (0.15 g, 43%) was prepared as a white powder: MS (ES)m/e 372 (M+H)⁺.

Example 85

[0805] Preparation of(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl]acrylamide

[0806] A solution of6-bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one(0.86 g, 3.00 mmole),N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (see Example 1 (a),0.68 g, 3.00 mmole), Pd(OAc)₂ (0.07 g, 0.30 mmole),tri-ortho-tolylphosphine (0.18 g, 0.60 mmole) and diisopropylethylamine(1.31 mL, 7.50 mmole) in propionitrile (50 mL) was deoxygenated, thenwas heated at reflux under N₂ overnight. The dark mixture was filteredthrough a pad of celite®, and the filter pad was rinsed withacetonitrile (250 mL). The filtrate was concentrated in vacuo, and theresidue was purified by flash chromatography on silica gel (10%EtOAc/EtOH). The title compound (0.46 g, 36%) was obtained as a lightyellow solid after drying in vacuo: MS (ES) m/e 434 (M+H)⁺.

Example 86

[0807] Preparation of(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-methoxycarbonvl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0808] According to the procedure of Example 15 (b), except substitutingmethyl(+)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-1,8-naphthyridine-3-carboxylate(2.5 g, 8.8 mmole), from Preparation 4 (d), for the5-bromo-2,2′-dipyridylamine, the title compound (1.82 g, 48%) wasprepared as an off-white solid: MS (ES) m/e 433.4 (M+H)⁺.

Example 87

[0809] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(1.3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methylacrylamide

[0810] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 88

[0811] Preparation of(E)-N-(1.3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0812] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 89

[0813] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)acrylamide

[0814] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 90

[0815] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)acrylamide

[0816] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 91

[0817] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)acrylamide

[0818] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 92

[0819] Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0820] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 93

[0821] Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0822] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 94

[0823] Preparation of(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0824] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 95

[0825] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-(benzofuran-3-ylmethyl)-N-methylacrylamide

[0826] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 96

[0827] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide

[0828] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 97

[0829] Preparation of(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)acrylamide

[0830] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 98

[0831] Preparation of(E)-N-(benzofuran-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0832] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 99

[0833] Preparation of(E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0834] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 100

[0835] Preparation of(E)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0836] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 101

[0837] Preparation of(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]acrylamide

[0838] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 102

[0839] Preparation of(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]acrylamide

[0840] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 103

[0841] Preparation of(E)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0842] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 104

[0843] Preparation of(E)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

[0844] The title compound is prepared following methods analogous tothose described in the previous preparations and examples.

Example 105

[0845] Parenteral Dosage Unit Composition

[0846] A preparation which contains 20 mg of the compound of Example 1as a sterile dry powder is prepared as follows: 20 mg of the compound isdissolved in 15 mL of distilled water. The solution is filtered understerile conditions into a 25 mL multi-dose ampoule and lyophilized. Thepowder is reconstituted by addition of 20 mL of 5% dextrose in water(D5W) for intravenous or intramuscular injection. The dosage is therebydetermined by the injection volume. Subsequent dilution may be made byaddition of a metered volume of this dosage unit to another volume ofD5W for injection, or a metered dose may be added to another mechanismfor dispensing the drug, as in a bottle or bag for IV drip infusion orother injection-infusion system.

Example 106

[0847] Oral Dosage Unit Composition

[0848] A capsule for oral administration is prepared by mixing andmilling 50 mg of the compound of Example 1 with 75 mg of lactose and 5mg of magnesium stearate. The resulting powder is screened and filledinto a hard gelatin capsule.

Example 107

[0849] Oral Dosage Unit Composition

[0850] A tablet for oral administration is prepared by mixing andgranulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50mg of the compound of Example 1 with a 10% gelatin solution. The wetgranules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3mg stearic acid; and compressed into a tablet.

[0851] The above description fully discloses how to make and use thepresent invention. However, the present invention is not limited to theparticular embodiments described hereinabove, but includes allmodifications thereof within the scope of the following claims. Thevarious references to journals, patents and other publications which arecited herein comprises the state of the art and are incorporated hereinby reference as though fully set forth.

What is claimed is:
 1. A compound according to formula (I):

wherein:

R¹ is H, C₁₋₄alkyl, —C₀₋₆alkyl-Ar, —(CH₂)₁₋₃N(R′)₂, or —(CH₂)₁₋₃OR; R²is H, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ is

R⁴ is H or C₁₋₄alkyl;

indicates that one of the two designated bonds is a double bond and theother is a single bond; R⁵ is CH₂ when the bond to which it is attachedis a double bond; or R⁵ is H or C₁₋₄alkyl when the bond to which it isattached is a single bond; R⁶ is H or C₁₋₄alkyl; each R⁷ independentlyis H, C₁₋₆alkyl, —C₀₋₆alkyl-Ar, —(CH₂)1-3N(R)₂, or —(CH₂)₁₋₃OR′; R⁸ is Hor C₁₋₄alkyl; R⁹ and R⁹′ independently are H or C₁₋₄alkyl; R¹⁰ isC₁₋₄alkyl, N(R)₂, NHC(O)R′, NHCH₂C(O)R′ or NHC(O)CH═CHR′; Y* is N(R)₂,NHC(O)R, NHCH₂C(O)R′ or NHC(O)CH═CHR′; each X independently is H,C₁₋₄alkyl, CH₂OH, OR′, SR′CN, N(R′)₂, CH₂N(R)₂, NO₂, CF₃, CO₂R′,CON(R)₂, COR′, NR′C(O)R, F, Cl, Br, I or —S(O)_(r)CF₃; X* is—(CH₂)₁₋₃C(O)N(R′)—(CH₂)₁₋₃-Ar or —(CH₂)₁₋₃C(O)N(R′)—(CH₂)₁₋₃-Het; W isS or O; Q is H or C₁₋₄alkyl; each R′ independently is H, C₁₋₆alkyl,—CO₀₋₆alkyl-Ar or —C₀₋₆alkyl-Het; and r is 0, 1 or 2; or apharmaceutically acceptable salt thereof.
 2. A compound of formula (II):

wherein:

R¹ is H or C₁₋₄alkyl; R² is H, C₁₋₄alkyl or C₃₋₆cycloalkyl; R³ is

R⁴ is H or C₁₋₄alkyl;

indicates that one of the two designated bonds is a double bond and theother is a single bond; R⁵ is CH₂ when the bond to which it is attachedis a double bond; or R⁵ is H or C₁₋₄alkyl when the bond to which it isattached is a single bond; R⁶ is H or C₁₋₄alkyl; R⁷ is H, C₁₋₆alkyl or—C₀₋₆alkyl-Ar; Y is H, C₁₋₄alkyl, N(R)₂, NHC(O)R′, NHCH₂C(O)R′ orNHC(O)CH═CHR′; each X independently is H, C₁₋₄alkyl, CH₂OH, OR′, SR, CN,N(R′)₂, CH₂N(R′)₂, NO₂, CF₃, CO₂R′, CON(R)₂, COR′, NR′C(O)R, F, Cl, Br,I or —S(O)_(r)CF₃; W is S or O; Q is H or C₁₋₄alkyl; M is CH₂ or O; L isCH₂ or C(O); E is O or NR′; each R′ independently is H, C₁₋₆alkyl or—C₀₋₆alkyl-Ar; and r is 0, 1 or 2; or a pharmaceutically acceptable saltthereof.
 3. A compound according to formula (III):

wherein: D¹ to D⁵ form an accessible substituted seven-membered ring,which may be saturated or unsaturated, optionally containing up to twoheteroatoms chosen from the group of O, S and N wherein S and N may beoptionally oxidized; R¹¹ is C₁₋₆alkyl; and R″ is H or C₁₋₆alkyl; or apharmaceutically acceptable salt thereof.
 4. A compound which is:(E)-3-(6-aminopyridin-3-yl)-N-(4,6-dichloro-1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide;(E)-3-(2-aminopyrimidin-5-yl)-N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(1-isopropyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-[6-(pyridin-2-ylamino)pyridin-3-yl]acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(3,3-dimethyl-3H-indene-1-ylmethyl)-N-methylacrylamide;(E)-3-(2-aminopyrimidin-5-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide;(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(2-methylbenzo[b]thiophen-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide;(E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide;(E)-3-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide;(E)-N-(1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(1H-indol-3-ylmethyl)-N-methylacrylamide(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;(E)-3-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylamide;(E)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide;(E)-N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(1)-3-[6-amino-5-[[N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)amino]carbonylethyl]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;(E)-N-(2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylamide;(E)-N-(1-ethyl-5-fluoro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(6-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(5-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-methyl-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;(E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide;(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide;(E)-2,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-[6-[N-(carboxymethyl)amino]pyridin-3-yl]-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-[N-(methylaminocarbonylmethyl)amino]pyridin-3-yl]acrylamide;(E)-3,N-dimethyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(7-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide;(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(7-chloro-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-(2-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(5-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(4-fluoro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(4-fluoro-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(7-carboxy-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-(1,7-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(1,6-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(1,4-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(3,3-dimethyl-3H-indene-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(1,5-dimethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(7-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(7-hydroxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;N-Methyl-N-(2-methyl-H-indol-3-ylmethyl)-3-(4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e]-1,4-diazepin-7-yl)acrylamide;(E)-N-[1-(2-hydroxyethyl)-1H-indol-3-ylmethyl]-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(4-chloro-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylamide;(E)-N-(4-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(5-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(naphthalen-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(quinolin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-(6-amino-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(1-ethyl-1H-indol-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(naphthalen-1-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-(benzofuran-2-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(6-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide;(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-[3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl]acrylamide;(E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methylacrylamide;(E)-N-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)acrylamide;(E)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-(benzofuran-3-ylmethyl)-N-methylacrylamide;(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide;(E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)acrylamide;(E)-N-(benzofuran-3-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-N-methyl-N-(2-methylbenzofuran-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]acrylamide;(E)-(6-aminopyridin-3-yl)-N-methyl-N-[1-(I-methyl-1H-indol-3-yl)ethyl]acrylamide;(E)-N-methyl-N-[1-(1-methyl-1H-indol-2-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;or(E)-N-methyl-N-[1-(1-methyl-1H-indol-3-yl)ethyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide;or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition which comprises a compound according to any one of claims1-4 and a pharmaceutically acceptable carrier.
 6. A method forinhibiting Fab I which comprises administering to a subject in needthereof a compound according to any one of claims 1-4.
 7. A method oftreating bacterial infections which comprises administering to a subjectin need thereof a compound according to any one of claims 1-4.
 8. Acompound according to any one of claims 1 to 4 for use as a medicament.9. The use of a compound as defined in claims 1-4 in the manufacture ofa medicament for the treatment of bacterial infections.
 10. The use of acompound as defined in claims 1-4 in the manufacture of a medicament forthe treatment of diseases in which inhibition of Fab I is indicated.